NM_001128849.1:c.3484G>A

SMARCA4 · NP_001122321.1:p.(Gly1162Ser) · NM_001128849.1

GRCh37: chr19:11141507 G>A · GRCh38: chr19:11030831 G>A

Gene: SMARCA4 Transcript: NM_001128849.1

Final call

Likely Pathogenic

PM1 moderate PM2 moderate PM5 moderate PP3 supporting

Variant details

Gene

SMARCA4

Transcript

NM_001128849.1

Protein

NP_001122321.1:p.(Gly1162Ser)

gnomAD AF

ClinVar

Tier I - Strong

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001128849.1:c.3484G>A (p.Gly1162Ser) is a missense variant in the SMARCA4 ATPase/helicase C-terminal domain, a well-established critical functional domain where pathogenic missense variants are enriched (PM1).

The variant is absent from all population databases, including gnomAD v2.1, v4.1, and gnomAD-Canada, with allele frequency of 0 (PM2).

A different missense change at the same codon, p.Gly1162Cys, has been experimentally demonstrated to cause loss of function in a systematic SMARCA4 functional characterization study (PM5).

Multiple lines of in silico evidence support a deleterious effect: REVEL score of 0.969 and BayesDel score of 0.592 both predict damaging consequences (PP3).

Per generic ACMG/AMP 2015 classification rules (PMID:25741868), the combination of three moderate criteria (PM1 + PM2 + PM5) meets the threshold for Likely Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Not met	PVS1 is not applicable: NM_001128849.1:c.3484G>A is a missense variant (p.Gly1162Ser). The generic PVS1 framework per PMC6185798 is restricted to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). This variant falls into the 'other' bucket and does not trigger PVS1.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No alternative nucleotide change producing the same p.Gly1162Ser amino acid substitution has been reported as pathogenic in ClinVar or the literature.	clinvar
PS2	Not met	No de novo occurrence data is available for this variant.
PS3	Not met	The exact variant p.Gly1162Ser was not directly tested in any functional study. PMID:33144586 tested p.Gly1162Cys at the same residue and demonstrated loss of function, but this is PM5 territory (same codon, different amino acid change) rather than PS3. A single residue tested at the same codon without systematic characterization of the full range does not satisfy PS3's requirement for variant-specific or systematic-range functional evidence.	PMID:33144586
PS4	Not met	No case-control data comparing variant prevalence in affected versus unaffected individuals is available. The ClinVar submission (1-star, single submitter) and COSMIC somatic count (n=14) do not constitute germline case-control evidence.	clinvar
PS5	Not met	No alternate molecular basis for disease has been identified in patients harboring this variant. No second pathogenic variant in SMARCA4 or another gene has been reported to explain disease in carriers.
PM1	Met	p.Gly1162Ser is located within the SMARCA4 ATPase/helicase C-terminal domain, a well-established critical functional domain. PMID:33144586 characterized multiple missense mutations across this domain (including adjacent residues G1159V and G1162C) and demonstrated that mutations in this region abrogate chromatin remodeling activity and are loss-of-function. The helicase domain is essential for SMARCA4 catalytic activity and is a known hotspot for pathogenic missense variants in Coffin-Siris syndrome and cancer predisposition.	PMID:33144586
PM2	Met	NM_001128849.1:c.3484G>A is absent from all population databases: gnomAD v2.1 (AF=0), gnomAD v4.1 (AF=0), and gnomAD-Canada v1.0 (AF=0). This meets PM2 (<0.1% allele frequency threshold per generic ACMG).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Met	A different missense change at the same codon, p.Gly1162Cys (c.3484G>T), was directly tested in PMID:33144586 and demonstrated to be loss-of-function. G1162C-expressing cells failed to rescue SMARCA2 depletion, had no detectable nucleosome remodeling activity, and exhibited dominant-negative chromatin effects. No ClinVar PM5 comparators were identified at this residue, but the literature provides functional evidence that a different missense at Gly1162 is pathogenic, satisfying PM5.	PMID:33144586
PM6	Not met	No de novo occurrence data with confirmed paternity and maternity is available for this variant.
PP1	Not met	No co-segregation data is available for this variant.
PP2	Not met	SMARCA4 has a mixed mutational spectrum: truncating variants cause rhabdoid tumor predisposition syndrome type 2 (RTPS2), while missense variants in the helicase domain cause Coffin-Siris syndrome (CSS). Without gnomAD missense constraint metrics (Z-score) in the evidence packet, PP2 cannot be applied to establish that SMARCA4 has a low rate of benign missense variation.
PP3	Met	Multiple lines of in silico evidence support a deleterious effect: REVEL score 0.969 (strongly pathogenic), BayesDel score 0.592 (elevated). SpliceAI predicts no splice impact (max delta score 0.00), consistent with a missense effect rather than splicing alteration. Two independent computational methods agree on a damaging prediction.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data is available for assessment. The variant is assessed without clinical context.
PP5	Not met	ClinVar review status is 'criteria provided, single submitter' (1-star). Per governing rules, PP5 is applied at supporting level only when ClinVar classification has 3-star expert panel (EP) review status. A 1-star ClinVar entry is insufficient for PP5.	clinvar
BA1	Not met	The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). Allele frequency is 0, far below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all population databases. Allele frequency is 0, far below the >0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observation in healthy adult individuals has been reported for this variant.
BS3	Not met	No well-established functional studies demonstrate a benign effect. The only functional data available (PMID:33144586) tested G1162C at the same residue and demonstrated loss of function, consistent with a deleterious effect, not benign.	PMID:33144586
BS4	Not met	No segregation data in affected families is available to evaluate lack of segregation.
BP1	Not met	BP1 does not apply: SMARCA4 disease is caused by both missense and truncating variants. Missense variants in the helicase domain cause Coffin-Siris syndrome, while truncating variants cause RTPS2. The gene does not have a mechanism limited to truncating variants only.
BP2	Not met	No observation in trans with a pathogenic variant has been reported.
BP4	Not met	Computational predictions are unanimously deleterious: REVEL 0.969 (strongly pathogenic), BayesDel 0.592 (elevated). BP4 applies when multiple lines of computational evidence suggest no impact, which is contradicted by the available scores.	revel bayesdel
BP5	Not met	No alternate molecular basis for disease has been identified in a case harboring this variant.
BP6	Not met	ClinVar classification is 'Tier I - Strong' (pathogenic/likely pathogenic), not benign. The single submitter (1-star) classified the variant as pathogenic. No reputable source reports this variant as benign.	clinvar
BP7	Not met	BP7 does not apply: c.3484G>A is a missense variant (p.Gly1162Ser), not a synonymous/silent variant. SpliceAI max delta score is 0.00, confirming no cryptic splice effect, but BP7 is restricted to synonymous variants for which splicing prediction algorithms predict no impact.	spliceai

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