rs1555795854

Variant names:

• chr19-11059747-G-GC
• rs1555795854
• NM_001387283.1:c.4732-3dupC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PVS1_Moderate PM2 BP6_Moderate

The NM_003072.5(SMARCA4):​c.4636-3dupC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_003072.5 splice_acceptor, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.670

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 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.026901295 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.6, offset of 0 (no position change), new splice context is: ccctggtgtctctgccccAGatc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 19-11059747-G-GC is Benign according to our data. Variant chr19-11059747-G-GC is described in ClinVar as [Likely_benign]. Clinvar id is 537892.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4732-3dupC		splice_acceptor_variant, intron_variant	Intron 33 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4636-3dupC		splice_acceptor_variant, intron_variant	Intron 32 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4732-6_4732-5insC		splice_region_variant, intron_variant	Intron 33 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4636-6_4636-5insC		splice_region_variant, intron_variant	Intron 32 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4642-6_4642-5insC		splice_region_variant, intron_variant	Intron 32 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4546-6_4546-5insC		splice_region_variant, intron_variant	Intron 32 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4546-6_4546-5insC		splice_region_variant, intron_variant	Intron 31 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4546-6_4546-5insC		splice_region_variant, intron_variant	Intron 31 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4543-6_4543-5insC		splice_region_variant, intron_variant	Intron 32 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4057-6_4057-5insC		splice_region_variant, intron_variant	Intron 29 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3286-6_3286-5insC		splice_region_variant, intron_variant	Intron 25 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3268-6_3268-5insC		splice_region_variant, intron_variant	Intron 24 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3130-6_3130-5insC		splice_region_variant, intron_variant	Intron 24 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2896-6_2896-5insC		splice_region_variant, intron_variant	Intron 22 of 24			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.700-6_700-5insC		splice_region_variant, intron_variant	Intron 5 of 7	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Benign:1

Sep 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555795854; hg19: chr19-11170423;