rs1555780058

Positions:

• chr19-11024441-GG-CA

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003072.5(SMARCA4):​c.3081+3_3081+4delGGinsCA variant causes a splice region, intron 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.352

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]

SMARCA4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant		ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant		ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant			NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant		1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant				ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant		5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant				ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant				ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant		5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2493+3_2493+4delGGinsCA		splice_region_variant, intron_variant				ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1725+3_1725+4delGGinsCA		splice_region_variant, intron_variant				ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1806+3_1806+4delGGinsCA		splice_region_variant, intron_variant				ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1566+3_1566+4delGGinsCA		splice_region_variant, intron_variant				ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1434+3_1434+4delGGinsCA		splice_region_variant, intron_variant				ENSP00000494159.1

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: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 21, 2023

This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 537829). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change falls in intron 21 of the SMARCA4 gene. It does not directly change the encoded amino acid sequence of the SMARCA4 protein. It affects a nucleotide within the consensus splice site. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2020

The c.3081+3_3081+4delGGinsCA intronic variant, located in intron 20 of the SMARCA4 gene, results from an in-frame from the deletion of two nucleotides and the insertion of two nucleotides at nucleotide position 3081. This nucleotide region is not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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: rs1555780058; hg19: chr19-11135117;