rs1555777830

Variant names:

• chr19-11019702-G-GTAAC
• rs1555777830
• NM_001387283.1:c.2616+2_2616+5dupTAAC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The ENST00000344626.10(SMARCA4):​c.2616+1_2616+2insTAAC variant causes a splice donor, intron 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 ENST00000344626.10 splice_donor, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.022451457 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9, offset of 0 (no position change), new splice context is: aagGTaact. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2616+2_2616+5dupTAAC		splice_region_variant, intron_variant	Intron 18 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2616+2_2616+5dupTAAC		splice_region_variant, intron_variant	Intron 18 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2616+1_2616+2insTAAC		splice_donor_variant, intron_variant	Intron 18 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2616+1_2616+2insTAAC		splice_donor_variant, intron_variant	Intron 18 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2616+1_2616+2insTAAC		splice_donor_variant, intron_variant	Intron 18 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2616+1_2616+2insTAAC		splice_donor_variant, intron_variant	Intron 19 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2616+1_2616+2insTAAC		splice_donor_variant, intron_variant	Intron 18 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2616+1_2616+2insTAAC		splice_donor_variant, intron_variant	Intron 18 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2616+1_2616+2insTAAC		splice_donor_variant, intron_variant	Intron 19 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2028+1_2028+2insTAAC		splice_donor_variant, intron_variant	Intron 15 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1260+1_1260+2insTAAC		splice_donor_variant, intron_variant	Intron 11 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1341+1_1341+2insTAAC		splice_donor_variant, intron_variant	Intron 11 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1101+1_1101+2insTAAC		splice_donor_variant, intron_variant	Intron 10 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.969+1_969+2insTAAC		splice_donor_variant, intron_variant	Intron 9 of 24			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Feb 24, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 18 of the SMARCA4 gene. It does not directly change the encoded amino acid sequence of the SMARCA4 protein, but it affects a nucleotide within the consensus splice site of the intron. 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555777830; hg19: chr19-11130378;