rs1555774702

Positions:

• chr19-11013001-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001387283.1(SMARCA4):​c.2329del​(p.Leu777TrpfsTer54) variant causes a frameshift 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_001387283.1 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.571

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]

(HGNC:):

ACMG classification

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 19-11013001-TC-T is Pathogenic according to our data. Variant chr19-11013001-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 537835.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.2329del	p.Leu777TrpfsTer54	frameshift_variant	16/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.2329del	p.Leu777TrpfsTer54	frameshift_variant	16/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2329del	p.Leu777TrpfsTer54	frameshift_variant	16/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.2329del	p.Leu777TrpfsTer54	frameshift_variant	16/35	1	NM_003072.5	P4
	ENST00000587831.1	n.29-1748del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 16, 2017

This variant has not been reported in the literature in individuals with SMARCA4-related disease. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SMARCA4 are known to be pathogenic (PMID: 24658001, 24658002). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu777Trpfs*54) in the SMARCA4 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1555774702; hg19: chr19-11123677;