rs1555780058

Variant names:

• chr19-11024441-GG-CA
• rs1555780058
• NM_001387283.1:c.3081+3_3081+4delGGinsCA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001387283.1(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. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_001387283.1 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.352
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant	Intron 21 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant	Intron 21 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant	Intron 21 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant	Intron 21 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant	Intron 21 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant	Intron 22 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant	Intron 21 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant	Intron 21 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3081+3_3081+4delGGinsCA		splice_region_variant, intron_variant	Intron 22 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2493+3_2493+4delGGinsCA		splice_region_variant, intron_variant	Intron 18 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1725+3_1725+4delGGinsCA		splice_region_variant, intron_variant	Intron 14 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1806+3_1806+4delGGinsCA		splice_region_variant, intron_variant	Intron 14 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1566+3_1566+4delGGinsCA		splice_region_variant, intron_variant	Intron 13 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1434+3_1434+4delGGinsCA		splice_region_variant, intron_variant	Intron 12 of 24			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

Feb 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). ClinVar contains an entry for this variant (Variation ID: 537829). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 18, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.35

Splicing

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

Other links and lift over

dbSNP: rs1555780058; hg19: chr19-11135117;