rs762962010

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_003073.5(SMARCB1):​c.607G>A​(p.Ala203Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000171 in 1,461,808 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.000017 ( 1 hom. )

Consequence

SMARCB1
NM_003073.5 missense

Scores

1
2
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 6.86
Variant links:
Genes affected
SMARCB1 (HGNC:11103): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) The protein encoded by this gene is part of a complex that relieves repressive chromatin structures, allowing the transcriptional machinery to access its targets more effectively. The encoded nuclear protein may also bind to and enhance the DNA joining activity of HIV-1 integrase. This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.3064434).
BS2
High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMARCB1NM_003073.5 linkc.607G>A p.Ala203Thr missense_variant Exon 5 of 9 ENST00000644036.2 NP_003064.2 Q12824-1
SMARCB1NM_001362877.2 linkc.661G>A p.Ala221Thr missense_variant Exon 5 of 9 NP_001349806.1
SMARCB1NM_001317946.2 linkc.634G>A p.Ala212Thr missense_variant Exon 5 of 9 NP_001304875.1 G5E975Q9H836
SMARCB1NM_001007468.3 linkc.580G>A p.Ala194Thr missense_variant Exon 5 of 9 NP_001007469.1 Q12824-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMARCB1ENST00000644036.2 linkc.607G>A p.Ala203Thr missense_variant Exon 5 of 9 NM_003073.5 ENSP00000494049.2 Q12824-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251280
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135828
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461808
Hom.:
1
Cov.:
34
AF XY:
0.0000179
AC XY:
13
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000198
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
Alfa
AF:
0.0000988
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 1 Uncertain:2
Mar 27, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Rhabdoid tumor predisposition syndrome 1;C3553248:Intellectual disability, autosomal dominant 15;C4048809:SMARCB1-related schwannomatosis Uncertain:1
Feb 13, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Dec 08, 2021
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The SMARCB1 c.607G>A (p.Ala203Thr) missense change has a maximum subpopulation frequency of 0.0035% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/22-24145588-G-A?dataset=gnomad_r2_1). Four of six in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533). To our knowledge, this variant has not been reported in individuals with rhabdoid tumor predisposition syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4, PP2. -

not provided Uncertain:1
Dec 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 203 of the SMARCB1 protein (p.Ala203Thr). This variant is present in population databases (rs762962010, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SMARCB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 340912). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SMARCB1 protein function with a negative predictive value of 80%. 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. -

SMARCB1-related schwannomatosis Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary cancer-predisposing syndrome Benign:1
Jan 06, 2021
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.087
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
23
DANN
Benign
0.94
DEOGEN2
Benign
0.23
.;T;T;.;T
Eigen
Benign
-0.42
Eigen_PC
Benign
-0.11
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.96
.;.;.;.;D
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.31
T;T;T;T;T
MetaSVM
Benign
-0.85
T
MutationAssessor
Benign
-1.8
.;N;.;.;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
1.9
N;.;N;.;N
REVEL
Benign
0.28
Sift
Benign
1.0
T;.;T;.;T
Sift4G
Benign
1.0
T;.;T;.;T
Polyphen
0.0
.;B;B;.;.
Vest4
0.58
MVP
0.24
MPC
1.3
ClinPred
0.24
T
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.39
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs762962010; hg19: chr22-24145588; COSMIC: COSV54098356; COSMIC: COSV54098356; API