rs1555755067

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_003072.5(SMARCA4):​c.982_986delCCGCA​(p.Pro328AspfsTer57) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

SMARCA4
NM_003072.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.65
Variant links:
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 Pathogenic. Variant got 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 19-10987785-CCACCG-C is Pathogenic according to our data. Variant chr19-10987785-CCACCG-C is described in ClinVar as [Pathogenic]. Clinvar id is 537779.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMARCA4NM_001387283.1 linkc.982_986delCCGCA p.Pro328AspfsTer57 frameshift_variant Exon 6 of 36 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkc.982_986delCCGCA p.Pro328AspfsTer57 frameshift_variant Exon 6 of 35 ENST00000344626.10 NP_003063.2 P51532-1A7E2E1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMARCA4ENST00000646693.2 linkc.982_986delCCGCA p.Pro328AspfsTer57 frameshift_variant Exon 6 of 36 NM_001387283.1 ENSP00000495368.1 Q9HBD4
SMARCA4ENST00000344626.10 linkc.982_986delCCGCA p.Pro328AspfsTer57 frameshift_variant Exon 6 of 35 1 NM_003072.5 ENSP00000343896.4 P51532-1
SMARCA4ENST00000643549.1 linkc.982_986delCCGCA p.Pro328AspfsTer57 frameshift_variant Exon 6 of 35 ENSP00000493975.1 A0A2R8Y4P4
SMARCA4ENST00000541122.6 linkc.982_986delCCGCA p.Pro328AspfsTer57 frameshift_variant Exon 7 of 35 5 ENSP00000445036.2 P51532-4
SMARCA4ENST00000643296.1 linkc.982_986delCCGCA p.Pro328AspfsTer57 frameshift_variant Exon 6 of 34 ENSP00000496635.1 P51532-4
SMARCA4ENST00000644737.1 linkc.982_986delCCGCA p.Pro328AspfsTer57 frameshift_variant Exon 6 of 34 ENSP00000495548.1 P51532-4
SMARCA4ENST00000589677.5 linkc.982_986delCCGCA p.Pro328AspfsTer57 frameshift_variant Exon 7 of 35 5 ENSP00000464778.1 P51532-3
SMARCA4ENST00000643995.1 linkc.394_398delCCGCA p.Pro132fs frameshift_variant Exon 3 of 32 ENSP00000496004.1 A0A2R8YGG3

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Pathogenic:1
Aug 22, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMARCA4-related disease. Loss-of-function variants in SMARCA4 are known to be pathogenic (PMID: 24658001, 24658002). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Pro328Aspfs*57) in the SMARCA4 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs1555755067; hg19: chr19-11098461; API