owencqueen/cgbench_data huggingface dataset:
Gene: GAMT (HGNC:4136)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Allele frequency >0.003 (0.3%) in gnomAD in any continental population in gnomAD with >2000 alleles.


GAMT specifications:




Any variant with a frequency >0.003 (based on the estimated prevalence 1 in 114,000, PMID 24071436) in gnomAD (max allelic contribution = 100%; max genetic contribution = 100%).


Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).
Gene: GAMT (HGNC:4136)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: GAMT (HGNC:4136)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Allele frequency >0.001 (0.1%) in gnomAD in any continental population in gnomAD with >2000 alleles. 


GAMT specifications:




Any variant with a frequency >0.001 (based on the estimated prevalence 1 in 114,000 (PMID: 24071436) in gnomAD (max allelic contribution = 40%; max genetic contribution = 100%).


Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).
Gene: GAMT (HGNC:4136)
Evidence Code: BS2 — Original ACMG Summary
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
Gene: GAMT (HGNC:4136)
Evidence Code: BS2 — Strong
Modification Type: None
Observed in the homozygous state in a healthy adult.
Gene: GAMT (HGNC:4136)
Evidence Code: BS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Gene: GAMT (HGNC:4136)
Evidence Code: BS3 — Supporting
Modification Type: Disease-specific,Strength
>30% normal GAA activity when the variant is expressed in a heterologous cell type.
GAMT specifications:
In vitro assays in which a variant is expressed in GAMT-deficient cultured cells (e.g. GAMT-deficient fibroblasts) or in-fusion High-Fidelity cloning of GAMT transcript and site directed mutagenesis to generate missense variant overexpressed in HeLa cells and measurement of GAMT activity in cells for wild-type and missense variant. Any variant with enzyme activity at or above 30% of normal in the following publications meets BS3_Supporting (Mercimek-Mahmutoglu et al, 2014; PMID 24415674; Mercimek-Mahmutoglu et al, 2016, PMID 26319512; DesRoches et al, 2016, PMID 26003046).
Gene: GAMT (HGNC:4136)
Evidence Code: BS4 — Original ACMG Summary
Lack of segregation in affected members of a family.
Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.
Gene: GAMT (HGNC:4136)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: GAMT (HGNC:4136)
Evidence Code: BP2 — Original ACMG Summary
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Gene: GAMT (HGNC:4136)
Evidence Code: BP2 — Supporting
Modification Type: None
Observed in cis with a pathogenic variant (to take AR inheritance into account).
Gene: GAMT (HGNC:4136)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: GAMT (HGNC:4136)
Evidence Code: BP4 — Original ACMG Summary
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.
Gene: GAMT (HGNC:4136)
Evidence Code: BP4 — Supporting
Modification Type: None
For missense changes, REVEL score <0.5.


For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.


For non-canonical splice site variants, use SpliceAI (
https://spliceailookup.broadinstitute.org/
 ) and varSEAK (
https://varseak.bio/
) to assess the impact of variants that are not +/-1 or 2 canonical splice site variants. For SpliceAI, this criterion can be applied for scores <0.2, and for varSEAK class 1 and 2. If there is any evidence for possible creation of a cryptic splice site, this criterion should not be applied.
Gene: GAMT (HGNC:4136)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: GAMT (HGNC:4136)
Evidence Code: BP6 — Original ACMG Summary
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
Gene: GAMT (HGNC:4136)
Evidence Code: BP7 — Original ACMG Summary
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Gene: GAMT (HGNC:4136)
Evidence Code: BP7 — Supporting
Modification Type: None
Apply this criterion as described.