NM_001128849.3:c.3894C>T is a synonymous variant (p.Asp1298=) in the SMARCA4 gene. Synonymous variants that do not alter splicing are typically benign.1 This variant is present in population databases at very low frequencies: gnomAD v2.1 (12/251,084 alleles, AF=0.0048%), gnomAD v4.1 (60/1,613,590 alleles, AF=0.0037%), and gnomAD-Canada (9/18,414 alleles, AF=0.049%). Population frequency alone is insufficient to classify this variant as benign or pathogenic by allele frequency thresholds.2 SpliceAI predicts no significant impact on splicing (max delta score 0.03), and the synonymous nucleotide substitution is not predicted to create or disrupt a splice site. This supports a benign interpretation under both BP4 and BP7.3 This variant has been reported in ClinVar as Likely benign by six clinical laboratories (ClinVar Variation ID: 238439). No laboratory has submitted a conflicting classification, supporting BP6.4 No published literature was identified that specifically describes NM_001128849.3:c.3894C>T. All PMIDs associated with ClinVar submissions refer to methodological or guideline publications that do not mention this variant. Applying generic ACMG/AMP 2015 combination rules (Richards et al., PMID:25741868): three supporting benign criteria are met (BP4, BP6, BP7) with no pathogenic criteria met. The combination of two or more supporting benign criteria is sufficient for a classification of Likely Benign.5
SMARCA4
Final classification
Likely Benign
BP4BP6BP7
SMARCA4
c.3894C>T
p.Asp1298=
This variant
NM_001128849.3:c.3894C>T is a synonymous variant (p.Asp1298=) in the SMARCA4 gene. Synonymous variants that do not alter splicing are typically benign.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 3 supporting benign, which maps to Likely Benign.
Classification rationale
BP4BP6BP7
Likely Benign
SMARCA4 c.3894C>T
BP4 + BP6 + BP7
→
Likely Benign
5
generic_acmg_combination_rules
Gene diagram
· NM_001128849.3 · variants mapped to exon structure
SMARCA4
NM_001128849.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BP4
supporting
Benign
Multiple lines of computational evidence support a benign interpretation. SpliceAI predicts no significant splice impact (max delta score 0.03). The variant is synonymous (p.Asp1298=) with no predicted effect on the primary amino acid sequence. The absence of REVEL and BayesDel scores is consistent with the synonymous nature of the variant and the inability of missense-focused tools to assess non-coding consequences.
SpliceAI max delta = 0.03 (no splicing impactwell below 0.1 threshold)Variant is synonymous with no predicted change to protein sequence
✓
BP6
supporting
Benign
This variant has been classified as Likely benign by six clinical laboratories in ClinVar (ClinVar Variation ID: 238439). While the review status is 'criteria provided, single submitter' and no expert panel review has been performed, the consistent classification across multiple independent clinical laboratories supports a benign interpretation under BP6.
ClinVar classification: Likely benign (6 clinical laboratories)Submitters include: Ambry GeneticsLabcorp Genetics (Invitae)
✓
BP7
supporting
Benign
BP7 is met: this is a synonymous variant (p.Asp1298=) at a nucleotide position where SpliceAI predicts no significant splice impact (max delta score 0.03, well below 0.1), and the nucleotide is not in a highly conserved splice consensus region. The variant falls in exon 28 (c.3874–3951) of the SMARCA4 transcript NM_001128849.3, distant from exon-intron boundaries.
Synonymous variant: c.3894C>Tp.Asp1298=SpliceAI max delta score = 0.03 (no splice site creation or disruption)
Assessed · not applied
· 17 not met · 0 not assessed
Pathogenic
PS2
No de novo observation data are available for this variant.
PS3
No well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product have been identified for this variant.
PS4
No case-control data or sufficient statistical evidence demonstrates significantly higher prevalence of this variant in affected individuals compared to controls.
PM1
This variant does not reside in a known mutational hotspot or critical functional domain with statistically significant enrichment of pathogenic variation.
PM2
This variant is present in multiple population databases (gnomAD v2.1: 12 alleles; v4.1: 60 alleles; gnomAD-Canada: 9 alleles) and is therefore not absent from controls.
PM6
No assumed de novo observation data are available.
PP1
No cosegregation data are available for this variant.
PP3
No in silico predictors support a pathogenic effect.
PP4
No patient phenotype data specific to this variant are available.
PP5
PP5 is not met: ClinVar reports this variant as Likely benign, not pathogenic.
Benign
BA1
BA1 is not met: the maximum allele frequency across population databases is approximately 0.0048% (gnomAD v2.1) to 0.049% (gnomAD-Canada), well below the 1% threshold required for BA1.
BS1
BS1 is not met: while the variant is observed in population databases, the maximum allele frequency (0.049% in gnomAD-Canada) remains below the 0.3% threshold required for BS1.
BS2
No data are available regarding observation of this variant in a healthy adult individual in trans with a dominant disorder, or in a homozygous state for a recessive disorder with no phenotype.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing have been identified for this variant.
BS4
No segregation or family data are available to assess lack of cosegregation with disease.
BP2
No data are available regarding observation of this variant in trans with a known pathogenic variant, or in cis with a pathogenic variant, in any individual.
BP5
No data are available demonstrating that this variant has been observed in a case with an alternative molecular basis for disease.
N/A · 6
PVS1 · PS1 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.71842e-05; MAF= 0.00372%, 60/1613590 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.83092e-05; MAF= 0.00483%, 57/1179900 alleles, homozygotes = 0); grpmax FAF= 3.775e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.77928e-05; MAF= 0.00478%, 12/251084 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108767; MAF= 0.01088%, 2/18388 alleles, homozygotes = 0); grpmax FAF= 4.747e-05.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0004887585532746823, 9/18414 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0037%
· 60 / 1,613,590
0 hom · FAF 0.0038%
0 hom · FAF 0.0038%
European (non-Finnish) 57 / 1,179,900 |
0.0048% |
East Asian 2 / 44,900 |
0.0045% |
Remaining individuals 1 / 62,484 |
0.0016% |
+ 7 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0048%
· 12 / 251,084
0 hom · FAF 0.0047%
0 hom · FAF 0.0047%
East Asian 2 / 18,388 |
0.011% |
European (non-Finnish) 10 / 113,440 |
0.0088% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
0.049%
· 9 / 18,414
0 hom · FAF 0.034%
0 hom · FAF 0.034%
Remaining individuals 1 / 1,138 |
0.088% |
European (non-Finnish) 8 / 11,736 |
0.068% |
+ 7 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, South Asian)
ClinVar
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories). (ClinVarID = 238439)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 5 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR