19-10986548-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_001387283.1(SMARCA4):c.715G>T(p.Gly239Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G239S) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SMARCA4
NM_001387283.1 missense
NM_001387283.1 missense
Scores
3
10
5
Clinical Significance
Conservation
PhyloP100: 4.59
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 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, SMARCA4
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.715G>T | p.Gly239Cys | missense_variant | 4/36 | ENST00000646693.2 | |
SMARCA4 | NM_003072.5 | c.715G>T | p.Gly239Cys | missense_variant | 4/35 | ENST00000344626.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.715G>T | p.Gly239Cys | missense_variant | 4/36 | NM_001387283.1 | |||
SMARCA4 | ENST00000344626.10 | c.715G>T | p.Gly239Cys | missense_variant | 4/35 | 1 | NM_003072.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1387604Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 684870
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1387604
Hom.:
Cov.:
34
AF XY:
AC XY:
0
AN XY:
684870
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
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Gnomad4 ASJ exome
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Gnomad4 EAS exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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Gnomad4 NFE exome
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Gnomad4 OTH exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 06, 2021 | This sequence change replaces glycine with cysteine at codon 239 of the SMARCA4 protein (p.Gly239Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 826871). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 21, 2018 | The p.G239C variant (also known as c.715G>T), located in coding exon 3 of the SMARCA4 gene, results from a G to T substitution at nucleotide position 715. The glycine at codon 239 is replaced by cysteine, an amino acid with highly dissimilar properties. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
Sift4G
Uncertain
D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D
Polyphen
D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D
Vest4
MutPred
Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);Gain of catalytic residue at P238 (P = 0.0499);
MVP
MPC
0.83
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at