Variant classification summary

NM_001128849.1:c.335C>T

SMARCA4 · NP_001122321.1:p.(Pro112Leu) · NM_001128849.1

GRCh37: chr19:11096061 C>T · GRCh38: chr19:10985385 C>T

Gene: SMARCA4 Transcript: NM_001128849.1

Final call

VUS

PM2 moderate

Variant details

Gene

SMARCA4

Transcript

NM_001128849.1

Protein

NP_001122321.1:p.(Pro112Leu)

gnomAD AF

1.858980237800752e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001128849.1:c.335C>T (p.Pro112Leu) is a missense variant in SMARCA4 identified in the germline context.

2

This variant is present at extremely low frequency in population databases (gnomAD v2.1: 1/31,372 alleles, 0.003%; gnomAD v4.1: 3/1,613,788 alleles, 0.0002%), meeting PM2 at moderate strength.

3

No functional studies, case-control data, segregation data, or de novo observations are available for this variant. In silico tools produce conflicting predictions (REVEL 0.609 pathogenic; BayesDel -0.0146 benign). ClinVar classification is Uncertain significance with single-submitter review status.

4

Only one moderate criterion (PM2) is met. Under generic ACMG/AMP 2015 combination rules, a single moderate criterion is insufficient to reach Likely pathogenic or Likely benign. The variant is classified as Uncertain significance.

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	Missense substitution (NM_001128849.1:c.335C>T, p.Pro112Leu); does not fall into null-variant categories (nonsense, frameshift, or canonical splice ±1,2). PVS1 decision framework not applied.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence that the same amino acid change (p.Pro112Leu) has been established as pathogenic via a different nucleotide change. No literature or database record identifies a pathogenic PS1-equivalent variant at this residue.	clinvar pm5_candidates
PS2	Not assessed	No de novo data available. No publications report this variant as a confirmed de novo occurrence.
PS3	Not met	No functional studies identified for NM_001128849.1:c.335C>T (p.Pro112Leu). OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. No publications with experimental functional data for this exact variant or a systematically characterized range including position 112 were found.	oncokb
PS4	Not assessed	No case-control studies or variant-specific case prevalence data available. ClinVar submissions (4 total, all single-submitter) do not provide detailed case-level phenotype information to support PS4.	clinvar
PS5	Not met	No different pathogenic missense change has been identified at the same residue (Pro112). PM5 candidate search returned no comparator variants. No literature evidence of a pathogenic missense at codon 112.	pm5_candidates clinvar
PM1	Not met	Position 112 in SMARCA4 lies in the N-terminal region outside characterized critical functional domains (QLQ, HSA, BRK, DExx helicase, HELICc, Bromodomain). Cancerhotspots.org does not identify this as a statistically significant residue. No mutational hotspot or critical functional domain evidence supports PM1.	oncokb
PM2	Met	This variant is present at extremely low frequency in population databases. gnomAD v2.1 AF=3.19e-05 (0.00319%, 1/31,372 alleles), gnomAD v4.1 AF=1.86e-06 (0.00019%, 3/1,613,788 alleles), both far below the 0.1% PM2 threshold. Absent from gnomAD-Canada. No homozygotes observed. Highest subpopulation frequency is African/African American at 0.0115% (v2.1) and 0.0040% (v4.1).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No same-residue pathogenic missense comparator variants identified at Pro112. Automated PM5 candidate harvesting returned no candidates; same-residue ClinVar search found no pathogenic missense at this position.	pm5_candidates
PM6	Not assessed	No de novo data available. PM6 requires a confirmed de novo observation with confirmed maternity/paternity.
PP1	Not assessed	No segregation data available. No family studies or cosegregation analysis reported for this variant.
PP2	Not assessed	Insufficient constraint data to apply PP2. While SMARCA4 missense variants are an established disease mechanism (Coffin-Siris syndrome), explicit gene-level missense constraint metrics (Z-score) were not available in the evidence brief. Cannot reliably determine whether the gene has a low rate of benign missense variation.
PP3	Not met	In silico tools produce conflicting predictions. REVEL score 0.609 suggests a deleterious effect, but BayesDel score -0.0146 is in the benign range. Multiple lines of computational evidence do not agree on a deleterious effect; PP3 requires concordant pathogenic predictions from multiple tools.	revel bayesdel
PP4	Not assessed	Patient phenotype information not available. Cannot assess whether the patient's phenotype is highly specific for SMARCA4-related disease.
PP5	Not met	ClinVar classification for this variant is Uncertain significance (3 clinical laboratories) and Likely benign (1 laboratory), all with criteria provided, single submitter review status. No expert panel (3-star) classification as pathogenic. PP5 requires reputable source classification as pathogenic; VUS does not meet this threshold.	clinvar
BA1	Not met	gnomAD allele frequency far below BA1 threshold of 1%. Highest observed AF is 0.0115% in African/African American (v2.1) and 0.0040% in African/African American (v4.1). This is not a common polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD allele frequency far below BS1 threshold of 0.3%. Highest observed AF is 0.0115% in African/African American (v2.1). Population frequency is not elevated above the benign threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Only 4 total allele observations across gnomAD v2+v4 combined (>1.6M alleles). For an autosomal dominant tumor predisposition syndrome (RTPS2) with onset often in infancy/childhood, observation in 3-4 individuals in population databases is insufficient to meet BS2, which requires observation in multiple healthy adults at an age when disease would be expected to manifest with full penetrance.	gnomad_v2 gnomad_v4
BS3	Not assessed	No functional studies available showing that this variant has no deleterious effect. BS3 requires experimental evidence demonstrating normal protein function.
BS4	Not assessed	No segregation data available to demonstrate lack of cosegregation with disease.
BP1	Not met	SMARCA4 missense variants are an established disease mechanism. Heterozygous missense variants in SMARCA4 cause Coffin-Siris syndrome, while truncating variants cause RTPS2. BP1 applies only to genes where primarily truncating variants cause disease; SMARCA4 has both missense and truncating as distinct disease mechanisms, so BP1 does not apply.	PMID:25741868 pvs1_gene_context
BP2	Not assessed	No data available on observation of this variant in trans with a known pathogenic variant. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP4	Not met	In silico tools produce conflicting predictions. REVEL score 0.609 suggests a deleterious effect. Only BayesDel (-0.0146) predicts benign. Multiple lines of computational evidence do not agree on a benign effect; BP4 requires multiple tools to predict no impact on the gene product.	revel bayesdel
BP5	Not assessed	No data available on an alternate molecular basis for disease in this individual.
BP6	Not met	ClinVar classification for this variant is Uncertain significance (3 labs) and Likely benign (1 lab), all with single-submitter review status. No expert panel classification as benign. BP6 requires a reputable source to classify as benign; VUS does not meet this threshold.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants where splicing is predicted to be unaffected. NM_001128849.1:c.335C>T is a missense variant (p.Pro112Leu), not synonymous.

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