Variant classification summary

NM_000520.6:c.1421+1G>C

HEXA · NP_000511.2:p.? · NM_000520.6

GRCh37: chr15:72638575 C>G · GRCh38: chr15:72346234 C>G

Gene: HEXA Transcript: NM_000520.6

Final call

Likely Pathogenic

PVS1 very strong PS3 moderate BP4 supporting

Variant details

Gene

HEXA

Transcript

NM_000520.6

Protein

NP_000511.2:p.?

gnomAD AF

6.759480326191436e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PVS1 very strong reflects a canonical splice-site loss-of-function variant in HEXA.

2

Likely Pathogenic: PS3 moderate is supported by patient-fibroblast cDNA studies showing intron 12 retention and abnormal HEXA mRNA.

3

Likely Pathogenic: BP4 supporting is met by SpliceAI max delta 0.00 but does not satisfy a benign rule.

Final determination: Under the generic ACMG/AMP 2015 rules, 1 very strong pathogenic criterion plus 1 moderate pathogenic criterion supports Likely Pathogenic; the applied BP4 supporting criterion does not satisfy a benign rule.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	Met at very strong: the canonical +1 splice variant in exon 12 of 14 is predicted to skip 91 coding nucleotides, shifting the reading frame in LOF-sensitive HEXA.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework PMID:2837213
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: affected patients were reported, but parental genotypes and confirmed maternity and paternity were not provided.	PMID:2837213
PS3	Met	Met at moderate strength: patient-fibroblast cDNA studies showed intron 12 retention and abnormal HEXA mRNA for the exact c.1421+1G>C splice variant.	PMID:2837213 PMID:2973464
PS4	Not assessed	Not assessed: affected-patient reports exist, but no exact-variant case-control counts or odds ratio with a 95% confidence interval are available.	PMID:2837213 PMID:2973464
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v2.1 total AF is 0.000115725, exceeding the recessive PM2 threshold of 0.0001 despite v4.1 being lower.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: affected patients had a normal sequence on the other allele, but no pathogenic variant in trans was documented for the PM3 requirement.	PMID:2837213
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a canonical splice-site variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: the report lacks an assumed-de-novo statement and provides no parental testing or inheritance information.	PMID:2837213
PP1	Not assessed	Not assessed: multiple affected patients were reported, but no shared family, pedigree, informative meioses, or co-segregation data were provided.	PMID:2837213
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.00 is below the >=0.2 PP3 supporting threshold for intronic or splice-region variants.	spliceai
PP4	Not assessed	Not assessed: literature reports classical infantile Tay-Sachs, but this case lacks the evaluated patient's phenotype or family-history details required for PP4.	PMID:2837213 PMID:2973464
PP5	Not met	Not met: ClinVar is Pathogenic without an expert-panel classification, consisting of ordinary laboratory submissions rather than a qualifying reputable expert assertion.	clinvar
BA1	Not met	Not met: gnomAD grpmax FAF is 2.47e-06 in v4.1, far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest filtering FAF is 7.03e-06, below the generic BS1 default threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 each report zero homozygotes, so no healthy adult homozygote is observed.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: available patient-fibroblast assays showed abnormal intron 12 retention, not normal HEXA splicing or preserved function.	PMID:2837213 PMID:2973464
BS4	Not assessed	Not assessed: no pedigree or affected relative lacking the variant was reported to demonstrate lack of segregation.	PMID:2837213
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no qualifying cis or dominant-disorder trans observation with a pathogenic variant was documented for BP2.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a canonical splice-site variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting: SpliceAI max delta 0.00 meets the <=0.1 BP4 threshold for intronic or splice-region variants.	spliceai
BP5	Not assessed	Not assessed: no evidence identifies an alternate molecular basis for disease in a case carrying this variant.	PMID:2837213 PMID:2973464
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign or likely benign classification is present, and ClinVar instead reports Pathogenic laboratory submissions.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules

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