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SMARCA4c.3484G>ALikely pathogenic
Print report
Variant interpretation report

SMARCA4 c.3484G>A, p.(Gly1162Ser)

NM_001128849.1:c.3484G>A NP_001122321.1:p.(Gly1162Ser) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About SMARCA4

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 4 Benign evidence criteria: 0
Pathogenic criteria applied · 4
PM1Moderate
PM1 · moderate

p.Gly1162Ser is located within the SMARCA4 ATPase/helicase C-terminal domain, a well-established critical functional domain. PMID:33144586 characterized multiple missense mutations across this domain (including adjacent residues G1159V and G1162C) and demonstrated that mutations in this region abrogate chromatin remodeling activity and are loss-of-function. The helicase domain is essential for SMARCA4 catalytic activity and is a known hotspot for pathogenic missense variants in Coffin-Siris syndrome and cancer predisposition.

PM2Moderate
PM2 · moderate

NM_001128849.1:c.3484G>A is absent from all population databases: gnomAD v2.1 (AF=0), gnomAD v4.1 (AF=0), and gnomAD-Canada v1.0 (AF=0). This meets PM2 (<0.1% allele frequency threshold per generic ACMG).

PM5Moderate
PM5 · moderate

A different missense change at the same codon, p.Gly1162Cys (c.3484G>T), was directly tested in PMID:33144586 and demonstrated to be loss-of-function. G1162C-expressing cells failed to rescue SMARCA2 depletion, had no detectable nucleosome remodeling activity, and exhibited dominant-negative chromatin effects. No ClinVar PM5 comparators were identified at this residue, but the literature provides functional evidence that a different missense at Gly1162 is pathogenic, satisfying PM5.

PP3Supporting
PP3 · supporting

Multiple lines of in silico evidence support a deleterious effect: REVEL score 0.969 (strongly pathogenic), BayesDel score 0.592 (elevated). SpliceAI predicts no splice impact (max delta score 0.00), consistent with a missense effect rather than splicing alteration. Two independent computational methods agree on a damaging prediction.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate, PM5 moderate, PP3 supporting; combination = 3 moderate + 1 supporting, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded. ClinVar API review status: criteria provided, single submitter.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SMARCA4, a tumor suppressor involved in chromatin remodeling, is recurrently altered in small cell carcinoma of the ovaries, hypercalcemic type (SCCOH

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
14 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV60788440, n = 14 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 4 met · 22 not met · 0 not assessed · 0 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001128849.1:c.3484G>A (p.Gly1162Ser) is a missense variant in the SMARCA4 ATPase/helicase C-terminal domain, a well-established critical functional domain where pathogenic missense variants are enriched (PM1).

The variant is absent from all population databases, including gnomAD v2.1, v4.1, and gnomAD-Canada, with allele frequency of 0 (PM2).

A different missense change at the same codon, p.Gly1162Cys, has been experimentally demonstrated to cause loss of function in a systematic SMARCA4 functional characterization study (PM5).

Multiple lines of in silico evidence support a deleterious effect: REVEL score of 0.969 and BayesDel score of 0.592 both predict damaging consequences (PP3).

Per generic ACMG/AMP 2015 classification rules (PMID:25741868), the combination of three moderate criteria (PM1 + PM2 + PM5) meets the threshold for Likely Pathogenic.

Met · 4

PM1 Moderatep.Gly1162Ser is located within the SMARCA4 ATPase/helicase C-terminal domain, a well-established critical functional domain. PMID:33144586 characterized multiple missense mutations across this domain (including adjacent residues G1159V and G1162C) and demonstrated that mutations in this region abrogate chromatin remodeling activity and are loss-of-function. The helicase domain is essential for SMARCA4 catalytic activity and is a known hotspot for pathogenic missense variants in Coffin-Siris syndrome and cancer predisposition. Details ▾Hide ▴
Evidence considered
  • Variant falls within the SMARCA4 ATPase/helicase C-terminal domain
  • functionally characterized as critical by PMID:33144586. Multiple pathogenic missense mutations cluster in this region.
Sources
PMID:33144586 ↗
PM2 ModerateNM_001128849.1:c.3484G>A is absent from all population databases: gnomAD v2.1 (AF=0), gnomAD v4.1 (AF=0), and gnomAD-Canada v1.0 (AF=0). This meets PM2 (<0.1% allele frequency threshold per generic ACMG). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • gnomAD v4.1 (exomes/genomes)
  • and gnomAD-Canada v1.0 (AF=0.0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PM5 ModerateA different missense change at the same codon, p.Gly1162Cys (c.3484G>T), was directly tested in PMID:33144586 and demonstrated to be loss-of-function. G1162C-expressing cells failed to rescue SMARCA2 depletion, had no detectable nucleosome remodeling activity, and exhibited dominant-negative chromatin effects. No ClinVar PM5 comparators were identified at this residue, but the literature provides functional evidence that a different missense at Gly1162 is pathogenic, satisfying PM5. Details ▾Hide ▴
Evidence considered
  • p.Gly1162Cys at the same codon was functionally tested and demonstrated LOF (PMID:33144586).
Sources
PMID:33144586 ↗
PP3 SupportingMultiple lines of in silico evidence support a deleterious effect: REVEL score 0.969 (strongly pathogenic), BayesDel score 0.592 (elevated). SpliceAI predicts no splice impact (max delta score 0.00), consistent with a missense effect rather than splicing alteration. Two independent computational methods agree on a damaging prediction. Details ▾Hide ▴
Evidence considered
  • REVEL=0.969 (high-confidence damaging prediction). BayesDel=0.592 (elevated). SpliceAI max delta=0.00 (no splice effect).
Still missing
  • HCI prior score not available.
Sources
revelbayesdelspliceai ↗

Not met · 22 · evaluated, threshold not reached

PVS1 PVS1 is not applicable: NM_001128849.1:c.3484G>A is a missense variant (p.Gly1162Ser). The generic PVS1 framework per PMC6185798 is restricted to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). This variant falls into the 'other' bucket and does not trigger PVS1. Details ▾Hide ▴
Evidence considered
  • Missense variant (p.Gly1162Ser)
  • not a null variant.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 No alternative nucleotide change producing the same p.Gly1162Ser amino acid substitution has been reported as pathogenic in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • No same-amino-acid pathogenic comparator identified at p.Gly1162Ser.
Sources
clinvar ↗
PS2 No de novo occurrence data is available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified.
Still missing
  • No de novo testing or family studies available.
PS3 The exact variant p.Gly1162Ser was not directly tested in any functional study. PMID:33144586 tested p.Gly1162Cys at the same residue and demonstrated loss of function, but this is PM5 territory (same codon, different amino acid change) rather than PS3. A single residue tested at the same codon without systematic characterization of the full range does not satisfy PS3's requirement for variant-specific or systematic-range functional evidence. Details ▾Hide ▴
Evidence considered
  • PMID:33144586 tested G1162C (not G1162S) at the same residue and found LOF. No variant-specific functional data for G1162S.
Still missing
  • No direct functional testing of p.Gly1162Ser.
Sources
PMID:33144586 ↗
PS4 No case-control data comparing variant prevalence in affected versus unaffected individuals is available. The ClinVar submission (1-star, single submitter) and COSMIC somatic count (n=14) do not constitute germline case-control evidence. Details ▾Hide ▴
Evidence considered
  • ClinVar 1-star classification does not provide case-control data. COSMIC somatic count of 14 is not germline evidence.
Still missing
  • No germline case-control studies.
Sources
clinvar ↗
PM6 No de novo occurrence data with confirmed paternity and maternity is available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified.
Still missing
  • No trio studies available.
PP1 No co-segregation data is available for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation studies identified.
Still missing
  • No family studies.
PP2 SMARCA4 has a mixed mutational spectrum: truncating variants cause rhabdoid tumor predisposition syndrome type 2 (RTPS2), while missense variants in the helicase domain cause Coffin-Siris syndrome (CSS). Without gnomAD missense constraint metrics (Z-score) in the evidence packet, PP2 cannot be applied to establish that SMARCA4 has a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
  • No missense constraint data available. SMARCA4 has both truncating and missense disease mechanisms.
Still missing
  • gnomAD missense constraint Z-score not available in evidence packet.
PP4 No patient phenotype or family history data is available for assessment. The variant is assessed without clinical context. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data provided.
Still missing
  • Patient phenotype and family history not available.
PP5 ClinVar review status is 'criteria provided, single submitter' (1-star). Per governing rules, PP5 is applied at supporting level only when ClinVar classification has 3-star expert panel (EP) review status. A 1-star ClinVar entry is insufficient for PP5. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 4530272: classification 'Tier I - Strong' but review status is 1-star (single submitter). Does not meet the 3-star EP threshold for PP5.
Sources
clinvar ↗
BA1 The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). Allele frequency is 0, far below the >1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0 in all gnomAD databases.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from all population databases. Allele frequency is 0, far below the >0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0 in all gnomAD databases.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No observation in healthy adult individuals has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No healthy adult carrier data available.
BS3 No well-established functional studies demonstrate a benign effect. The only functional data available (PMID:33144586) tested G1162C at the same residue and demonstrated loss of function, consistent with a deleterious effect, not benign. Details ▾Hide ▴
Evidence considered
  • PMID:33144586 tested G1162C (same codon) and found LOF
  • not benign effect.
Sources
PMID:33144586 ↗
BS4 No segregation data in affected families is available to evaluate lack of segregation. Details ▾Hide ▴
Evidence considered
  • No family segregation studies identified.
Still missing
  • No family studies.
BP1 BP1 does not apply: SMARCA4 disease is caused by both missense and truncating variants. Missense variants in the helicase domain cause Coffin-Siris syndrome, while truncating variants cause RTPS2. The gene does not have a mechanism limited to truncating variants only. Details ▾Hide ▴
Evidence considered
  • SMARCA4 has dual disease mechanisms: missense (Coffin-Siris syndrome) and truncating (RTPS2). PMID:41568967 confirms genotype-phenotype correlation with LoF variants causing RTPS and missense variants causing CSS.
BP2 No observation in trans with a pathogenic variant has been reported. Details ▾Hide ▴
Evidence considered
  • No trans-phase data available.
BP4 Computational predictions are unanimously deleterious: REVEL 0.969 (strongly pathogenic), BayesDel 0.592 (elevated). BP4 applies when multiple lines of computational evidence suggest no impact, which is contradicted by the available scores. Details ▾Hide ▴
Evidence considered
  • REVEL=0.969 and BayesDel=0.592 both predict deleterious effect
  • contrary to BP4 requirements.
Sources
revelbayesdel
BP5 No alternate molecular basis for disease has been identified in a case harboring this variant. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis identified.
BP6 ClinVar classification is 'Tier I - Strong' (pathogenic/likely pathogenic), not benign. The single submitter (1-star) classified the variant as pathogenic. No reputable source reports this variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar classification is pathogenic-range ('Tier I - Strong')
  • not benign.
Sources
clinvar ↗
BP7 BP7 does not apply: c.3484G>A is a missense variant (p.Gly1162Ser), not a synonymous/silent variant. SpliceAI max delta score is 0.00, confirming no cryptic splice effect, but BP7 is restricted to synonymous variants for which splicing prediction algorithms predict no impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous. SpliceAI max delta=0.00 confirms no splice impact but does not make BP7 applicable.
Sources
spliceai ↗
PS5 No alternate molecular basis for disease has been identified in patients harboring this variant. No second pathogenic variant in SMARCA4 or another gene has been reported to explain disease in carriers. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis identified.

Identifiers

Gene
SMARCA4
Transcript
NM_001128849.1
Coding (HGVS c.)
NM_001128849.1:c.3484G>A
Protein (HGVS p.)
NP_001122321.1:p.(Gly1162Ser)
GRCh38
chr19:11030831 G>A
GRCh37
chr19:11141507 G>A
ClinVar
4530272
COSMIC
COSV60788440

Gene diagram

Every interpreted variant in SMARCA4, mapped onto the exon structure of NM_001128849.1. Select a row to find it on the plot.

SMARCA4NM_001128849.1
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -19 bp
0.000
SpliceAI acceptor gainat -174 bp
0.000
SpliceAI donor lossat -203 bp
0.000
SpliceAI donor gainat +62 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.969
BayesDel
0.592

How the predictions were used

PP3 SupportingMultiple lines of in silico evidence support a deleterious effect: REVEL score 0.969 (strongly pathogenic), BayesDel score 0.592 (elevated). SpliceAI predicts no splice impact (max delta score 0.00), consistent with a missense effect rather than splicing alteration. Two independent computational methods agree on a damaging prediction. Details ▾Hide ▴
Evidence considered
  • REVEL=0.969 (high-confidence damaging prediction). BayesDel=0.592 (elevated). SpliceAI max delta=0.00 (no splice effect).
Still missing
  • HCI prior score not available.
Sources
revelbayesdelspliceai ↗
BP4 Computational predictions are unanimously deleterious: REVEL 0.969 (strongly pathogenic), BayesDel 0.592 (elevated). BP4 applies when multiple lines of computational evidence suggest no impact, which is contradicted by the available scores. Details ▾Hide ▴
Evidence considered
  • REVEL=0.969 and BayesDel=0.592 both predict deleterious effect
  • contrary to BP4 requirements.
Sources
revelbayesdel
BP7 BP7 does not apply: c.3484G>A is a missense variant (p.Gly1162Ser), not a synonymous/silent variant. SpliceAI max delta score is 0.00, confirming no cryptic splice effect, but BP7 is restricted to synonymous variants for which splicing prediction algorithms predict no impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous. SpliceAI max delta=0.00 confirms no splice impact but does not make BP7 applicable.
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.969. BayesDel score = 0.591961.

7 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

  • Functional characterization of SMARCA4 variants identified by targeted exome-sequencing of 131,668 cancer patients.
    Systematic functional characterization of SMARCA4 missense variants from 131,668 cancer patients. The study tested 14 helicase domain variants including G1162C at the same codon (Gly1162), which demonstrated complete loss of chromatin remodeling activity, inability to induce gene expression, and failure to rescue SMARCA2 depletion. G1162S was not directly tested or reported. The study provides domain-level evidence for PM1 and same-codon evidence for PM5.
    → PM1 → PM5 Does not name this variant
    PMID 33144586 ↗
    Source detail
    The majority of SMARCA4 mutants tested were unable to rescue SMARCA2 knockdown, confirming that these mutants (K785R, E882K, T910M, R1135W, G1162C, R1192C, G1232S) are indeed loss-of-function (LOF).

    Location Results: 'SMARCA4 missense mutants have reduced remodeling activity'; Fig. 5a; cell line NCI-H1435 harbors homozygous G1162C

    Context FRET nucleosome remodeling assay, ATAC-seq, qChIP, and clonogenic growth rescue in SMARCA4-deficient NCI-H1944 and A549 cell lines

Other recorded publications

  • Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer.
    Describes a chemistry-first drug discovery approach for personalized lung cancer treatment using a panel of 96 NSCLC cell lines. NM_001128849.1:c.3484G>A (p.Gly1162Ser) was not identified in this paper.
    Does not name this variant
    PMID 29681454 ↗
  • The genetic landscape of the childhood cancer medulloblastoma.
    Parsons DW et al. · 2011
    Comprehensive exome sequencing of 22 medulloblastomas identifying MLL2/MLL3 mutations as recurrent drivers. SMARCA4 was among genes sequenced but NM_001128849.1:c.3484G>A (p.Gly1162Ser) was not reported in the mutation tables.
    Does not name this variant
    PMID 21163964 ↗
  • Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.
    Pugh TJ et al. · 2012
    Medulloblastoma exome sequencing in 92 tumor-normal pairs identifying subtype-specific mutations. SMARCA4 was among 5 genes (CTNNB1, DDX3X, SMARCA4, TP53, CTDNEP1) selected for confirmatory sequencing, but NM_001128849.1:c.3484G>A was not reported.
    Does not name this variant
    PMID 22820256 ↗
  • Dissecting the genomic complexity underlying medulloblastoma.
    Jones DT et al. · 2012
    Whole-genome and whole-exome sequencing of 125 medulloblastomas as part of the ICGC PedBrain Tumor Project. SMARCA4 mutations were identified in medulloblastoma but NM_001128849.1:c.3484G>A was not reported.
    Does not name this variant
    PMID 22832583 ↗
  • Study of chromatin remodeling genes implicates SMARCA4 as a putative player in oncogenesis in neuroblastoma.
    Bellini A et al. · 2019
    Analysis of chromatin remodeling gene mutations in 283 neuroblastoma patients. SMARCA4 was identified as a putative player in neuroblastoma oncogenesis but NM_001128849.1:c.3484G>A was not specifically reported.
    Does not name this variant
    PMID 31018240 ↗
  • Novel mutations target distinct subgroups of medulloblastoma.
    Robinson G et al. · 2012
    Whole-genome sequencing of 37 medulloblastomas identifying recurrent mutations in 41 genes including SMARCA4. SMARCA4 mutations were found in medulloblastoma subgroups but NM_001128849.1:c.3484G>A was not reported.
    Does not name this variant
    PMID 22722829 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 4530272)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.969. BayesDel score = 0.591961.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SMARCA4, a tumor suppressor involved in chromatin remodeling, is recurrently altered in small cell carcinoma of the ovaries, hypercalcemic type (SCCOH

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV60788440, n = 14 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.