rs764152134
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBP6
The NM_003072.5(SMARCA4):c.3799G>A(p.Gly1267Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000513 in 779,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000016 ( 0 hom. )
Consequence
SMARCA4
NM_003072.5 missense
NM_003072.5 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 3.86
Genes affected
SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ 6.8459 (greater than the threshold 3.09). Trascript score misZ 8.7957 (greater than threshold 3.09). GenCC has associacion of gene with uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.2387389).
BP6
Variant 19-11033791-G-A is Benign according to our data. Variant chr19-11033791-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 480652.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.3799G>A | p.Gly1267Ser | missense_variant | 27/36 | ENST00000646693.2 | NP_001374212.1 | |
SMARCA4 | NM_003072.5 | c.3799G>A | p.Gly1267Ser | missense_variant | 27/35 | ENST00000344626.10 | NP_003063.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.3799G>A | p.Gly1267Ser | missense_variant | 27/36 | NM_001387283.1 | ENSP00000495368.1 | |||
SMARCA4 | ENST00000344626.10 | c.3799G>A | p.Gly1267Ser | missense_variant | 27/35 | 1 | NM_003072.5 | ENSP00000343896.4 | ||
SMARCA4 | ENST00000643995.1 | c.3211G>A | p.Gly1071Ser | missense_variant | 24/32 | ENSP00000496004.1 | ||||
SMARCA4 | ENST00000644963.1 | c.2443G>A | p.Gly815Ser | missense_variant | 20/28 | ENSP00000495599.1 | ||||
SMARCA4 | ENST00000642350.1 | c.2284G>A | p.Gly762Ser | missense_variant | 19/27 | ENSP00000495355.1 | ||||
SMARCA4 | ENST00000643857.1 | c.2152G>A | p.Gly718Ser | missense_variant | 18/25 | ENSP00000494159.1 | ||||
SMARCA4 | ENST00000643549.1 | c.3774+274G>A | intron_variant | ENSP00000493975.1 | ||||||
SMARCA4 | ENST00000541122.6 | c.3774+274G>A | intron_variant | 5 | ENSP00000445036.2 | |||||
SMARCA4 | ENST00000643296.1 | c.3774+274G>A | intron_variant | ENSP00000496635.1 | ||||||
SMARCA4 | ENST00000644737.1 | c.3774+274G>A | intron_variant | ENSP00000495548.1 | ||||||
SMARCA4 | ENST00000589677.5 | c.3774+274G>A | intron_variant | 5 | ENSP00000464778.1 | |||||
SMARCA4 | ENST00000644065.1 | c.2499+274G>A | intron_variant | ENSP00000493615.1 | ||||||
SMARCA4 | ENST00000538456.4 | c.30+274G>A | intron_variant | 3 | ENSP00000495197.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000408 AC: 1AN: 245330Hom.: 0 AF XY: 0.00000746 AC XY: 1AN XY: 134082
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GnomAD4 exome AF: 0.00000159 AC: 1AN: 627620Hom.: 0 Cov.: 0 AF XY: 0.00000292 AC XY: 1AN XY: 341942
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74322
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 16 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1267 of the SMARCA4 protein (p.Gly1267Ser). This variant is present in population databases (rs764152134, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 480652). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;.;N;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;.;.;.
REVEL
Uncertain
Sift
Benign
T;.;T;.;.;.
Sift4G
Benign
T;.;T;T;.;.
Polyphen
D;D;D;D;.;.
Vest4
MutPred
Loss of glycosylation at S1266 (P = 0.0239);Loss of glycosylation at S1266 (P = 0.0239);Loss of glycosylation at S1266 (P = 0.0239);Loss of glycosylation at S1266 (P = 0.0239);.;.;
MVP
MPC
1.4
ClinPred
T
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at