rs587777461

Positions:

• chr19-11035133-G-A
• chr19-11035133-G-C
• chr19-11035133-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_003072.5(SMARCA4):​c.4170+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_003072.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.87

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 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04409385 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11035133-G-A is Pathogenic according to our data. Variant chr19-11035133-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 139440.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4170+1G>A		splice_donor_variant, intron_variant		ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4170+1G>A		splice_donor_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.4170+1G>A		splice_donor_variant, intron_variant			NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4170+1G>A		splice_donor_variant, intron_variant		1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4071+1G>A		splice_donor_variant, intron_variant				ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4071+1G>A		splice_donor_variant, intron_variant		5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4071+1G>A		splice_donor_variant, intron_variant				ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4071+1G>A		splice_donor_variant, intron_variant				ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4071+1G>A		splice_donor_variant, intron_variant		5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3582+1G>A		splice_donor_variant, intron_variant				ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2814+1G>A		splice_donor_variant, intron_variant				ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2796+1G>A		splice_donor_variant, intron_variant				ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2655+1G>A		splice_donor_variant, intron_variant				ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2523+1G>A		splice_donor_variant, intron_variant				ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.327+1G>A		splice_donor_variant, intron_variant		3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777461; hg19: chr19-11145809; COSMIC: COSV60810020; COSMIC: COSV60810020;