Variant classification summary

NM_001128849.1:c.1333C>T

SMARCA4 · NP_001122321.1:p.(Gln445Ter) · NM_001128849.1

GRCh37: chr19:11101913 C>T · GRCh38: chr19:10991237 C>T

Gene: SMARCA4 Transcript: NM_001128849.1

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

SMARCA4

Transcript

NM_001128849.1

Protein

NP_001122321.1:p.(Gln445Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001128849.1:c.1333C>T (p.Gln445Ter) is a nonsense variant in exon 8 of SMARCA4, a gene with an established loss-of-function disease mechanism for rhabdoid tumor predisposition syndrome type 2 and Coffin-Siris syndrome, satisfying PVS1 at very strong strength under the ClinGen SVI framework (PMC6185798).

2

This variant is absent from all queried population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying PM2 at moderate strength.

3

The variant is absent from ClinVar and has not been reported in any curated clinical database, consistent with a rare variant of uncertain prevalence in affected populations.

4

No variant-specific functional studies, de novo observations, case-control data, or cosegregation evidence were identified for this variant in the available literature.

5

Applying generic ACMG/AMP 2015 combination rules, the evidence totals 10 points (PVS1 very_strong = 8 points; PM2 moderate = 2 points), meeting the threshold for a Pathogenic classification (>=10 points).

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	Met	NM_001128849.1:c.1333C>T is a nonsense variant (p.Gln445Ter) in exon 8 of 35 in SMARCA4, a gene in which loss of function is an established mechanism for germline disease (rhabdoid tumor predisposition syndrome type 2, Coffin-Siris syndrome). The premature stop codon at position 445 of 1,647 amino acids is predicted to trigger nonsense-mediated decay, resulting in a null allele. Under the ClinGen SVI PVS1 framework (PMC6185798), nonsense variants in genes with established LoF disease mechanisms qualify for PVS1 at full strength.	pvs1_generic_framework gnomad_v2 gnomad_v4
PS1	N/A	PS1 requires a different amino acid change at the same residue as a known pathogenic missense variant. This is a nonsense variant (p.Gln445Ter); no same-residue missense comparator is applicable.
PS2	Not met	No confirmed de novo observation with verified parentage was identified for NM_001128849.1:c.1333C>T in the available literature, ClinVar, or exploratory evidence search results.	clinvar PMID:24658002
PS3	Not met	No variant-specific experimental functional studies were identified for c.1333C>T. OncoKB classifies Q445* as Likely Oncogenic/Likely Loss-of-function, but this represents a curated knowledgebase annotation based on variant type inference, not direct experimental functional evidence meeting the PS3 threshold for germline variant classification.	oncokb
PS4	Not met	No case-control study comparing the prevalence of c.1333C>T in affected versus healthy populations is available. The variant's absence from gnomAD supports rarity but is captured under PM2 rather than PS4. The low incidence of SMARCA4-related disorders precludes formal case-control analysis.	gnomad_v2 gnomad_v4 gnomad_canada
PS5	N/A	PS5 requires the variant to be reported as pathogenic by a reputable source where the evidence is not available for independent evaluation. This variant is absent from ClinVar and has no prior classification from any external source.	clinvar
PM1	Not met	The variant at codon 445 lies in the N-terminal region of SMARCA4, outside any well-defined critical functional domain. The ATPase catalytic domain spans residues 757-1,564. The variant does not reside in a statistically significant mutational hotspot per CancerHotspots, and no variant-specific domain-based evidence supports PM1.	PMID:24658002
PM2	Met	NM_001128849.1:c.1333C>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 criterion for absence from population databases under generic ACMG/AMP 2015 guidelines. The allele frequency of 0.0 across all queried population cohorts is well below the 0.1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue. This variant is nonsense (p.Gln445Ter); the pm5_candidates search yielded zero same-residue comparator variants and the recommendation level is not_applicable.	pm5_candidates
PM6	Not met	No de novo observation (assumed or confirmed) was identified for c.1333C>T. The exploratory evidence search noted a possible ClinVar record (VCV000427319) that might contain de novo submissions, but direct ClinVar query for this variant returned no results. PM6 cannot be applied without at least one de novo report.	clinvar
PP1	Not met	No published cosegregation data for c.1333C>T with disease in multiple affected family members was identified. Most SMARCA4 germline mutations reported in the literature are de novo events; familial cases with documented segregation are rare and none involve this specific variant.	PMID:24658002
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is a nonsense variant; PP2 is not applicable to truncating variants.
PP3	Not assessed	For a nonsense variant, the deleterious effect is already captured by PVS1. BayesDel score of 0.66 for this position is above the deleterious threshold, and SpliceAI predicts no splicing impact (max delta = 0.01). In silico scores for a nonsense variant are considered redundant with PVS1 and are not independently applied under standard ACMG/AMP practice to avoid double-counting.	bayesdel spliceai
PP4	Not assessed	No patient-specific phenotype or family history information was provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology, which cannot be evaluated without clinical data.
PP5	N/A	PP5 requires a reputable source to have recently reported the variant as pathogenic. This variant is absent from ClinVar and has no prior classification from any external source.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0.0 and does not approach the 1% BA1 threshold required for a stand-alone benign classification.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all queried population databases. Allele frequency of 0.0 does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No evidence of observation of c.1333C>T in healthy adults was identified. The variant is absent from all population databases including gnomAD, which includes ostensibly healthy individuals.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating a neutral or benign effect were identified for c.1333C>T. The five literature_pass papers (PMID:18301784, 24658001, 24658002, 24658004, 25060813) discuss SMARCA4 at the gene level without providing variant-specific benign functional evidence.	PMID:24658002
BS4	Not met	No evidence of non-segregation with disease was identified. BS4 requires documentation that an affected individual does not carry the variant, which is not available.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. This variant is a truncating (nonsense) change; BP1 does not apply to null variants.
BP2	Not met	No observation of c.1333C>T in trans with a known pathogenic SMARCA4 variant in a healthy individual has been reported. Furthermore, SMARCA4-related disorders exhibit incomplete penetrance and variable expressivity, limiting the applicability of BP2 even if such an observation were available.
BP3	N/A	BP3 applies to in-frame insertions or deletions in repetitive regions. This is a single-nucleotide substitution variant; BP3 is not applicable.
BP4	Not met	Multiple lines of computational evidence do not suggest a benign effect. The BayesDel score of 0.66 exceeds the deleterious threshold (>0.5), arguing against BP4. SpliceAI predicts no splicing impact (max delta = 0.01), but this alone is insufficient to satisfy the multiple-lines-of-evidence requirement for BP4.	bayesdel spliceai
BP5	Not met	No observation of c.1333C>T in a case with an alternate molecular basis for disease was identified. BP5 requires a documented alternate cause in an affected individual carrying this variant.
BP6	N/A	BP6 requires a reputable source to have reported the variant as benign. This variant is absent from ClinVar and has no prior benign classification from any external source.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. This is a nonsense (stop-gain) variant; BP7 is not applicable.
PM3	N/A	PM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. SMARCA4-related conditions (RTPS2, Coffin-Siris syndrome) are autosomal dominant; PM3 is not applicable.
PM4	N/A	PM4 applies to nonstop or elongation variants resulting from stop-loss or in-frame changes. This is a substitution variant causing a premature stop codon (nonsense), not protein elongation. PM4 is not applicable.

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