rs190432371
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_003079.5(SMARCE1):c.487C>T(p.Arg163Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,613,202 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R163H) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
SMARCE1
NM_003079.5 missense
NM_003079.5 missense
Scores
6
7
5
Clinical Significance
Conservation
PhyloP100: 6.21
Genes affected
SMARCE1 (HGNC:11109): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily e, member 1) The protein encoded by this gene is part of the large ATP-dependent chromatin remodeling complex SWI/SNF, which is required for transcriptional activation of genes normally repressed by chromatin. The encoded protein, either alone or when in the SWI/SNF complex, can bind to 4-way junction DNA, which is thought to mimic the topology of DNA as it enters or exits the nucleosome. The protein contains a DNA-binding HMG domain, but disruption of this domain does not abolish the DNA-binding or nucleosome-displacement activities of the SWI/SNF complex. Unlike most of the SWI/SNF complex proteins, this protein has no yeast counterpart. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCE1 | NM_003079.5 | c.487C>T | p.Arg163Cys | missense_variant | 7/11 | ENST00000348513.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCE1 | ENST00000348513.12 | c.487C>T | p.Arg163Cys | missense_variant | 7/11 | 1 | NM_003079.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152072Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250798Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135534
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461010Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12AN XY: 726774
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74390
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial meningioma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 163 of the SMARCE1 protein (p.Arg163Cys). This variant is present in population databases (rs190432371, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SMARCE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 532250). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMARCE1 protein function. 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 04, 2023 | The p.R163C variant (also known as c.487C>T), located in coding exon 6 of the SMARCE1 gene, results from a C to T substitution at nucleotide position 487. The arginine at codon 163 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant has been detected in multiple individuals with no reported features of Coffin-Siris syndrome (Ambry internal data). Missense and in-frame variants in SMARCE1 are known to cause neurodevelopmental disorders; however, such associations with increased risk of meningiomas are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Smith JM et al. Nat Genet. 2013 Mar;45(3):295-8). Based on the supporting evidence, the association of this alteration with an increased risk of meningiomas is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Benign
T;.;.;.;.;.;.;.;.;T;.;.;T;.;.;.;.;.;.;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.;.;M;.;.;.;.;M;.;M;.;.;.;M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
REVEL
Benign
Sift
Uncertain
D;.;.;.;.;.;.;.;T;.;.;.;D;.;.;.;.;.;.;.;.
Sift4G
Uncertain
T;.;.;.;.;T;.;D;D;.;.;.;T;T;.;.;.;.;.;.;.
Polyphen
D;.;.;.;.;.;.;.;.;D;.;.;D;.;.;.;.;.;.;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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