Variant classification summary

NM_001001524.3:c.499G>A

TM6SF2 · NP_001001524.2:p.(Glu167Lys) · NM_001001524.3

GRCh37: chr19:19379549 C>T · GRCh38: chr19:19268740 C>T

Gene: TM6SF2 Transcript: NM_001001524.3

Final call

Benign

BA1 stand-alone benign BP4 supporting

Variant details

Gene

TM6SF2

Transcript

NM_001001524.3

Protein

NP_001001524.2:p.(Glu167Lys)

gnomAD AF

0.07088209101544862 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Benign: BA1 stand-alone benign is met by the high population allele frequency.

2

Benign: BP4 supporting is met because REVEL 0.075 is below the 0.29 threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, BA1 alone satisfies the Benign classification rule; the additional BP4 supporting criterion is concordant.

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	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no established pathogenic same-amino-acid change at Glu167 is documented, and the exact variant is absent from ClinVar.	clinvar spliceai
PS2	Not assessed	Not assessed: no documented proband phenotype, family-history status, or confirmed maternity and paternity with the variant absent in both parents.
PS3	Not assessed	Not assessed: no variant-specific in vitro or in vivo functional study or validated assay result was available.
PS4	Not assessed	Not assessed: gnomAD v4.1 AF is 0.0708821, but no affected-case/control counts or OR/RR with a 95% CI are available.	gnomad_v4
PM1	Not met	Not met: Glu167 has no Cancer Hotspots result, and no well-established critical domain with absent benign variation is documented.	hotspots cosmic
PM2	Not met	Not met: gnomAD non-cancer AF is 0.0590–0.0653, far above the PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected proband, pathogenic allele in trans, parental phase testing, or established recessive TM6SF2 disorder context is documented.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no different missense change at Glu167 has been determined pathogenic in the available clinical or literature evidence.	clinvar pm5_candidates
PM6	Not assessed	Not assessed: no documented assumed de novo occurrence, affected proband, parental genotypes, or family-history assessment is available.
PP1	Not assessed	Not assessed: zero affected relatives, informative meioses, genotype results, and segregation analysis are documented for the variant.
PP2	Not assessed	Not assessed: gene-wide benign missense constraint and a common missense disease mechanism are not established by the available evidence.	gnomad_v2 gnomad_v4
PP3	Not met	Not met: REVEL 0.075 is below the generic PP3 supporting threshold of 0.644 for this missense variant.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history is available to establish a highly specific single-gene disease presentation.
PP5	Not met	Not met: ClinVar has no exact-variant record, so no expert-panel pathogenic or likely pathogenic classification supports PP5.	clinvar
BA1	Met	Met: gnomAD grpmax FAF is 0.0867–0.0890, above the 0.05 BA1 threshold, with the relevant South Asian population exceeding 2,000 observed alleles.	gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: grpmax FAF is 0.0867–0.0890, but no disorder-specific prevalence, penetrance, allelic heterogeneity, or maximum-credible-frequency calculation is available.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 4,135 homozygotes, but population data do not establish healthy adult status or the required early-onset full penetrance.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific in vitro or in vivo functional study or validated assay result was available.
BS4	Not assessed	Not assessed: no tested affected family members or genotype-phenotype discordance is documented to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: the available evidence does not establish that TM6SF2 disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no individual-level genotype or phase data show a pathogenic variant in trans or cis, and no qualifying fully penetrant dominant TM6SF2 disorder is established.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting: REVEL 0.075 is below the generic BP4 supporting threshold of 0.29 for this missense variant.	revel
BP5	Not assessed	Not assessed: no case-level alternate molecular diagnosis is documented for a patient carrying this variant.
BP6	Not met	Not met: ClinVar has no exact-variant record, so no expert-panel benign or likely benign classification supports BP6.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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