NM_001128849.3:c.3894C>T

SMARCA4 · NP_001122321.1:p.(Asp1298=) · NM_001128849.3

GRCh37: chr19:11144819 C>T · GRCh38: chr19:11034143 C>T

Gene: SMARCA4 Transcript: NM_001128849.3

Final call

Likely Benign

BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

SMARCA4

Transcript

NM_001128849.3

Protein

NP_001122321.1:p.(Asp1298=)

gnomAD AF

3.7184166981699194e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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: NM_001128849.3:c.3894C>T is a synonymous variant (p.Asp1298=) and does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). Variant-specific PVS1 assessment confirms apply_generic_pvs1_framework=false, variant_bucket=other.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	PS1 is not applicable: this is a synonymous variant with no amino acid change. PS1 requires a nucleotide change producing the same amino acid change as a previously established pathogenic missense variant.
PS2	Not met	No de novo observation data are available for this variant. PS2 requires confirmation of de novo occurrence with both maternity and paternity confirmed.
PS3	Not met	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	Not met	No case-control data or sufficient statistical evidence demonstrates significantly higher prevalence of this variant in affected individuals compared to controls.
PS5	N/A	PS5 is not applicable: this is a synonymous variant with no amino acid change. PS5 applies only to novel missense variants at an amino acid residue where a different missense change has been established as pathogenic.
PM1	Not met	This variant does not reside in a known mutational hotspot or critical functional domain with statistically significant enrichment of pathogenic variation. Hotspot analysis confirms no residue-level significance, and OncoKB lists no established oncogenic hotspots at this position.	oncokb
PM2	Not met	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. While the allele frequency is very low (~0.0048% overall), PM2 requires absence from population databases for dominant disorders. The variant is observed across diverse populations and datasets, inconsistent with the absence criterion.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 is not applicable: this variant resolves to a synonymous change (p.Asp1298=) rather than a missense alteration. PM5 requires a novel missense change at the same amino acid residue as another pathogenic missense variant. The PM5 candidate analysis confirms inability to parse missense residue context from the normalized protein consequence.	pm5_candidates
PM6	Not met	No assumed de novo observation data are available. PM6 requires the variant to be assumed de novo with maternity and paternity not confirmed. No de novo context was reported in ClinVar submissions or the literature reviewed.
PP1	Not met	No cosegregation data are available for this variant. PP1 requires demonstration of cosegregation with disease in multiple affected family members.
PP2	N/A	PP2 is not applicable: this is a synonymous variant, not a missense change. PP2 applies specifically to missense variants in genes where missense variation is a common mechanism of disease and benign missense variation is rare.
PP3	Not met	No in silico predictors support a pathogenic effect. SpliceAI shows a maximum delta score of 0.03, well below the threshold for splice-altering prediction. REVEL and BayesDel scores are not available for this synonymous variant, which is expected as these tools are designed for missense substitutions.	spliceai
PP4	Not met	No patient phenotype data specific to this variant are available. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	PP5 is not met: ClinVar reports this variant as Likely benign, not pathogenic. PP5 requires a reputable source to have recently reported the variant as pathogenic. The six clinical laboratory submissions in ClinVar unanimously classify this variant as Likely benign.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	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. No homozygous observations are reported in gnomAD.
BS3	Not met	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	Not met	No segregation or family data are available to assess lack of cosegregation with disease. BS4 requires demonstration that the variant does not segregate with disease in affected family members.
BP1	N/A	BP1 is not applicable: this is a synonymous variant, not a missense change. BP1 applies specifically to missense variants in genes where truncating variants are the primary known mechanism of disease.
BP2	Not met	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.
BP3	N/A	Skipped per task specification: BP3 applies to in-frame deletions/insertions in repetitive regions, which is not relevant to this single-nucleotide synonymous substitution.
BP4	Met	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
BP5	Not met	No data are available demonstrating that this variant has been observed in a case with an alternative molecular basis for disease. BP5 requires identification of an alternate causal variant in a case where this variant is also present.
BP6	Met	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
BP7	Met	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.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.