rs1555875892

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_003073.5(SMARCB1):​c.137_140dupGATA​(p.Tyr47fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y47Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

SMARCB1
NM_003073.5 frameshift, stop_gained

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.12

Publications

0 publications found
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]
SMARCB1 Gene-Disease associations (from GenCC):
  • Coffin-Siris syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • intellectual disability, autosomal dominant 15
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • rhabdoid tumor predisposition syndrome 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
  • SMARCB1-related schwannomatosis
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
  • familial multiple meningioma
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial rhabdoid tumor
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • schwannomatosis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • complex neurodevelopmental disorder
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 22-23791797-G-GAGAT is Pathogenic according to our data. Variant chr22-23791797-G-GAGAT is described in ClinVar as Pathogenic. ClinVar VariationId is 464322.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMARCB1NM_003073.5 linkc.137_140dupGATA p.Tyr47fs frameshift_variant, stop_gained Exon 2 of 9 ENST00000644036.2 NP_003064.2 Q12824-1
SMARCB1NM_001362877.2 linkc.137_140dupGATA p.Tyr47fs frameshift_variant, stop_gained Exon 2 of 9 NP_001349806.1
SMARCB1NM_001317946.2 linkc.137_140dupGATA p.Tyr47fs frameshift_variant, stop_gained Exon 2 of 9 NP_001304875.1 G5E975Q9H836
SMARCB1NM_001007468.3 linkc.137_140dupGATA p.Tyr47fs frameshift_variant, stop_gained Exon 2 of 9 NP_001007469.1 Q12824-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMARCB1ENST00000644036.2 linkc.137_140dupGATA p.Tyr47fs frameshift_variant, stop_gained Exon 2 of 9 NM_003073.5 ENSP00000494049.2 Q12824-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Jan 16, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in SMARCB1 are known to be pathogenic (PMID: 10521299, 21208904). A different variant, c.141C>A, with the same effect (p.Tyr47*) has been reported in an individual with rhabdoid tumors (PMID: 21108436). This sequence change inserts 4 nucleotides in exon 2 of the SMARCB1 mRNA (c.137_140dupGATA), causing a frameshift at codon 47. This creates a premature translational stop signal (p.Tyr47*) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
3.1
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

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

Publications

Other links and lift over

dbSNP: rs1555875892; hg19: chr22-24133984; API