NM_001128849.1:c.4927G>T

SMARCA4 · NP_001122321.1:p.(Gly1643Cys) · NM_001128849.1

GRCh37: chr19:11170783 G>T · GRCh38: chr19:11060107 G>T

Gene: SMARCA4 Transcript: NM_001128849.1

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

SMARCA4

Transcript

NM_001128849.1

Protein

NP_001122321.1:p.(Gly1643Cys)

gnomAD AF

6.447378431455986e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant is extremely rare in population databases, present in gnomAD v4.1 at an allele frequency of 6.4×10⁻⁷ (1/1,551,018 alleles, no homozygotes) and absent from gnomAD v2.1, meeting PM2 at supporting strength.

Multiple computational predictors suggest no deleterious effect: REVEL score 0.414 (below pathogenic threshold), BayesDel score -0.086 (benign), and SpliceAI predicts no splice impact (max delta 0.0), meeting BP4 at supporting benign strength.

This variant is a missense substitution (p.Gly1643Cys) located in the extreme C-terminal region of SMARCA4, outside the bromodomain (~aa 1488-1590) and helicase domains. PVS1 is not applicable. No functional domain hotspot or established pathogenic comparator at this residue was identified (PM1 and PM5 not met).

ClinVar classifies this variant as Uncertain significance (1-star, single submitter). No pathogenic or benign assertions from expert panels are available (PP5 and BP6 not met).

Overall, the evidence is limited and conflicting: one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met. Per generic ACMG/AMP 2015 combination rules (PMID:25741868), this does not reach the threshold for Likely Pathogenic (≥2 supporting pathogenic), Likely Benign (≥2 supporting benign), or any higher classification tier. The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	PVS1 is not applicable: this is a missense variant (p.Gly1643Cys) and does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants). Generic PVS1 framework assessment was not triggered.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence of an alternate nucleotide change at codon 1643 resulting in the same amino acid substitution (p.Gly1643Cys) that has been previously established as pathogenic.
PS2	Not assessed	No de novo data available for this variant. Parental testing results are not present in the case materials or literature.
PS3	Not assessed	No functional studies were identified for this variant or a systematically characterized range that includes p.Gly1643. OncoKB reports no variant-specific reviewed functional evidence.	oncokb
PS4	Not met	The variant has not been observed at significantly increased frequency in affected individuals compared to general population controls. A single ClinVar submission from Ambry Genetics classifies it as VUS with no detailed case-level phenotypic information provided.	clinvar
PS5	Not met	No previously established pathogenic variant at codon 1643 with a different amino acid change was identified to satisfy the PS5 requirement for same-residue alternate pathogenic change.
PM1	Not met	The variant lies at p.Gly1643 in the extreme C-terminal region of SMARCA4, outside of characterized functional domains: the bromodomain ends at approximately p.1590 and the helicase domain ends at approximately p.1165. Cancerhotspots.org does not identify this residue as a statistically significant hotspot, and no literature identifies a well-characterized critical functional domain spanning this position.
PM2	Met	This variant is extremely rare in population databases: absent from gnomAD v2.1 and present in gnomAD v4.1 at an allele frequency of 6.4×10⁻⁷ (1/1,551,018 alleles, 0 homozygotes), well below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 candidate search was unable to confirm classic same-residue PM5 semantics; no same-residue comparator variants with pathogenic classifications were identified at p.Gly1643 in ClinVar.	pm5_candidates
PM6	Not assessed	No de novo data available for this variant. No report of confirmed de novo occurrence in any source.
PP1	Not assessed	No segregation data available for this variant. No family studies or cosegregation analysis present in the case materials.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation (typically Z-score >3.09) where missense variants are a common disease mechanism. SMARCA4 missense variants cause Coffin-Siris syndrome, but gene-level constraint data (HCI Prior) is not available for SMARCA4. Without evidence of a low rate of benign missense variation, PP2 cannot be applied.
PP3	Not met	Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.414 (below the 0.5 threshold for pathogenic prediction), BayesDel score is -0.086 (benign range), and SpliceAI predicts no splice impact (max delta = 0.0). The majority of available computational tools suggest a neutral or non-deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No proband phenotype or clinical information is available in the case materials to evaluate whether the patient's phenotype is specific for SMARCA4-related disease.
PP5	Not met	PP5 requires a pathogenic assertion from a reputable source (typically ClinVar 3-star expert panel). This variant is classified as Uncertain significance in ClinVar with 1-star review status (criteria provided, single submitter by Ambry Genetics). The automatic PP5 supporting rule for 3-star expert panel submissions does not apply at this review tier.	clinvar
BA1	Not met	The variant allele frequency in gnomAD v4.1 is 6.4×10⁻⁷ (0.00006%), far below the 1% BA1 threshold. BA1 requires AF >1% in any population.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires allele frequency greater than expected for the disorder (>0.3% for non-VCEP). The variant AF is 6.4×10⁻⁷, well below this threshold.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation in healthy adults with full penetrance expected at an early age. Only 1 heterozygous individual identified in gnomAD v4.1 out of 1.55M alleles; no homozygous observations. This is insufficient to establish the variant as benign in healthy controls.	gnomad_v4
BS3	Not met	No in vitro or in vivo functional studies demonstrating no deleterious effect of p.Gly1643Cys were identified. OncoKB reports no variant-specific functional evidence.	oncokb
BS4	Not assessed	No segregation data available to assess lack of cosegregation with disease in affected families.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease. SMARCA4 has a dual disease mechanism: truncating variants cause rhabdoid tumor predisposition syndrome type 2 (RTPS2) via loss of function, while missense variants (particularly in the helicase domain) cause Coffin-Siris syndrome via dominant-negative or gain-of-function effects. Since missense variants are a recognized disease mechanism in SMARCA4, BP1 does not apply.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic variant in SMARCA4. BP2 applies to recessive disorders; SMARCA4-related conditions are autosomal dominant.
BP4	Met	Multiple lines of computational evidence suggest no deleterious impact: REVEL score 0.414 (below the 0.5 threshold for pathogenicity), BayesDel score -0.086 (benign range), and SpliceAI max delta 0.0 (no predicted splice alteration). Three independent in silico predictors support a neutral or benign effect.	revel bayesdel spliceai
BP5	Not met	BP5 requires the variant be observed in an affected individual with an alternate molecular basis for disease. No such observation is available for this variant. The sole ClinVar submission does not report an alternate molecular diagnosis.
BP6	Not met	BP6 requires a benign assertion from a reputable source (typically ClinVar 3-star expert panel). This variant is classified as Uncertain significance with 1-star review status; it is not asserted as Benign or Likely Benign by any submitter.	clinvar
BP7	N/A	BP7 applies only to synonymous (silent) variants. This is a missense variant (c.4927G>T, p.Gly1643Cys), so BP7 is not applicable.

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