Variant classification summary

NM_000520.6:c.1274_1277dup

HEXA · NP_000511.2:p.(Tyr427IlefsTer5) · NM_000520.6

GRCh37: chr15:72638920 G>GGATA · GRCh38: chr15:72346579 G>GGATA

Gene: HEXA Transcript: NM_000520.6

Final call

Pathogenic

PVS1 very strong PS3 strong PM3 moderate PP4 supporting

Variant details

Gene

HEXA

Transcript

NM_000520.6

Protein

NP_000511.2:p.(Tyr427IlefsTer5)

gnomAD AF

0.0005378102942342771 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 (very strong) reflects a premature truncating HEXA frameshift in a loss-of-function disease mechanism.

2

Pathogenic: PS3 (strong) reflects demonstrated degradation of the mutant HEXA transcript through nonsense-mediated decay.

3

Pathogenic: PM3 (moderate) reflects the variant occurring in trans with disease-associated p.Arg178His in an affected patient.

4

Pathogenic: PP4 (supporting) reflects confirmed subacute Tay-Sachs disease in a patient carrying the exact variant.

Final determination: Under the generic ACMG/AMP 2015 fallback, one very strong pathogenic criterion plus one strong pathogenic criterion supports Pathogenic; PVS1 and PS3 meet this rule, with PM3 and PP4 adding further pathogenic evidence.

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, very strong: exon-11 c.1274_1277dup causes p.(Tyr427IlefsTer5), a premature truncation before the final exon in a HEXA loss-of-function disease mechanism.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework PMID:16352452 PMID:22441121
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: one affected patient lacked parental genotype data, while the two tested brothers were carriers rather than affected individuals, so confirmed de novo status is unavailable.	PMID:22441121 PMID:16352452
PS3	Met	Met, strong: patient-cell and minigene studies showed the mutant HEXA transcript was nearly undetectable and restored to approximately 40% of normal by translation inhibition.	PMID:11463833 PMID:10571007
PS4	Not met	Not met: exploratory OR 2.26 (95% CI 0.31-16.59) is below the >5.0 threshold and the confidence interval includes 1.0.	PMID:22441121 gnomad_v4
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 shows AF 0.00053781, above the supplied PM2 threshold of <=0.0001, despite zero observed homozygotes.	gnomad_v2 gnomad_v4
PM3	Met	Met: an affected Tay-Sachs patient was compound heterozygous for c.1274_1277dupTATC and the disease-associated c.533G>A (p.R178H) allele.	PMID:22441121
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: an affected patient was reported without parental results, but the available records do not establish that the variant was assumed de novo.	PMID:22441121 PMID:16352452
PP1	Not assessed	Not assessed: no multiple affected relatives with variant-positive segregation are documented; the two reported brothers were carriers, and the affected cohort case had no family segregation data.	PMID:16352452 PMID:22441121
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: this is a frameshift variant, outside PP3's missense and intronic/synonymous/splice-region computational scope.	pvs1_variant_assessment
PP4	Met	Met at supporting strength: the exact variant was reported in a patient with confirmed subacute Tay-Sachs disease, a highly specific HEXA-related phenotype.	PMID:22441121
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel classification, and the available literature can be independently evaluated.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF was 0.00029506, far below the 0.05 BA1 threshold despite a 0.0132095 Ashkenazi Jewish popmax point estimate.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest qualifying grpmax FAF was 0.00033447, below the generic BS1 threshold of 0.01, so frequency is not greater than expected.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: zero homozygotes are reported across available gnomAD all-comers and non-cancer subsets, whereas recessive BS2 requires a healthy adult homozygote.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated study shows absence of damage, while available evidence instead demonstrates mutant HEXA transcript degradation.	PMID:11463833 PMID:16352452
BS4	Not assessed	Not assessed: no informative affected relative tested negative for the variant, so lack of segregation cannot be demonstrated.	PMID:16352452 PMID:22441121
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
BP2	Not met	Not met: the reported relationship is trans in recessive Tay-Sachs, whereas BP2 requires cis pathogenic co-occurrence or trans observation in a fully penetrant dominant disorder.	PMID:22441121
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: this is a frameshift variant, so a no-impact splice prediction cannot support BP4 or negate its truncating protein effect.	pvs1_variant_assessment
BP5	Not met	Not met: the reported second variant is another HEXA allele, not an alternate molecular basis for the Tay-Sachs phenotype.	PMID:22441121
BP6	Not met	Not met: no exact-variant expert-panel benign or likely benign classification is present in ClinVar or the reviewed literature.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a frameshift variant.	generic_acmg_combination_rules

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