Variant classification summary

NM_001128849.1:c.3067G>T

SMARCA4 · NP_001122321.1:p.(Glu1023Ter) · NM_001128849.1

GRCh37: chr19:11135100 G>T · GRCh38: chr19:11024424 G>T

Gene: SMARCA4 Transcript: NM_001128849.1

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

SMARCA4

Transcript

NM_001128849.1

Protein

NP_001122321.1:p.(Glu1023Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PVS1 very strong supports a loss-of-function effect from the premature stop and expected nonsense-mediated decay.

2

Likely Pathogenic: PM2 supporting is met because the variant is absent from gnomAD v2.1 and v4.1.

Final determination: Under the generic ACMG/AMP 2015 fallback, one very strong criterion plus one supporting criterion supports a Likely Pathogenic classification.

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: nonsense c.3067G>T creates p.Glu1023Ter in exon 21 of a 1680-residue protein, with downstream coding exons supporting nonsense-mediated decay.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:24658001 PMID:24658002
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001128849.1:c.3067G>T in SMARCA4 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001122321.1:p.(Glu1023Ter). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented proband de novo observation or confirmed parental testing is available for this SMARCA4 variant.
PS3	Not assessed	Not assessed: no study directly tests c.3067G>T/p.Glu1023Ter in a validated functional assay.	PMID:18301784 PMID:24658001 PMID:24658002 PMID:24658004 PMID:25060813
PS4	Not assessed	Not assessed: no exact-variant case-control counts or enrichment statistic are available to evaluate PS4.
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001128849.1:c.3067G>T in SMARCA4 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001122321.1:p.(Glu1023Ter). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met, supporting: the variant is absent from gnomAD v2.1 and v4.1, giving observed frequency 0 versus the PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation or documented pathogenic SMARCA4 variant in trans is available for this variant.
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001128849.1:c.3067G>T in SMARCA4 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001122321.1:p.(Glu1023Ter). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001128849.1:c.3067G>T in SMARCA4 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001122321.1:p.(Glu1023Ter). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no unconfirmed de novo occurrence, affected proband, or parental testing information is documented for this SMARCA4 variant.
PP1	Not assessed	Not assessed: no informative relatives, variant-status results, affected meioses, or segregation pattern are documented for this SMARCA4 variant.
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001128849.1:c.3067G>T in SMARCA4 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001122321.1:p.(Glu1023Ter). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	N/A	Not applicable: the variant is a nonsense change, p.(Glu1023Ter), outside PP3's missense and splice-region calibration scope.
PP4	Not assessed	Not assessed: the affected individual's phenotype and a disease-specific phenotype match are not provided.
PP5	Not assessed	Not assessed: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification for PP5.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with observed allele frequency 0 versus the BA1 threshold of >=0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report the variant absent, with frequency 0 versus the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 show no carriers or homozygotes, so no healthy-individual observation supports BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no study demonstrates preserved function for c.3067G>T/p.Glu1023Ter in a validated assay.	PMID:18301784 PMID:24658001 PMID:24658002 PMID:24658004 PMID:25060813
BS4	Not assessed	Not assessed: no unaffected carriers or informative non-segregating meioses are documented for this SMARCA4 variant.
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001128849.1:c.3067G>T in SMARCA4 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001122321.1:p.(Glu1023Ter). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no documented pathogenic variant in trans or cis, with phase established, is available for this variant.
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001128849.1:c.3067G>T in SMARCA4 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001122321.1:p.(Glu1023Ter). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: the variant is a nonsense change, p.(Glu1023Ter), outside BP4's missense and splice-region calibration scope.
BP5	Not assessed	Not assessed: no alternative molecular diagnosis or criterion-specific BP5 evidence is documented for the patient.
BP6	Not assessed	Not assessed: ClinVar has no exact-variant expert-panel Benign or Likely benign classification for BP6.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001128849.1:c.3067G>T in SMARCA4 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001122321.1:p.(Glu1023Ter). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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