19-10995004-A-G

Variant names:

• chr19-10995004-A-G
• rs1555762222
• NM_001387283.1:c.1593+3A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003072.5(SMARCA4):​c.1593+3A>G 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. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 splice_region, intron
• Scores: Splicing: ADA: 0.8718
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.00600

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1593+3A>G		splice_region_variant, intron_variant	Intron 9 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1593+3A>G		splice_region_variant, intron_variant	Intron 9 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1593+3A>G		splice_region_variant, intron_variant	Intron 9 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1593+3A>G		splice_region_variant, intron_variant	Intron 9 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1593+3A>G		splice_region_variant, intron_variant	Intron 9 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1593+3A>G		splice_region_variant, intron_variant	Intron 10 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1593+3A>G		splice_region_variant, intron_variant	Intron 9 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1593+3A>G		splice_region_variant, intron_variant	Intron 9 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1593+3A>G		splice_region_variant, intron_variant	Intron 10 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1005+3A>G		splice_region_variant, intron_variant	Intron 6 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.237+3A>G		splice_region_variant, intron_variant	Intron 2 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.321+3A>G		splice_region_variant, intron_variant	Intron 2 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.81+3A>G		splice_region_variant, intron_variant	Intron 1 of 26			ENSP00000495355.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Jun 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 486476). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 9 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

May 01, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1593+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 8 in the SMARCA4 gene. This nucleotide position is well conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. 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
BayesDel_noAF	Benign	-0.80
CADD	Pathogenic	31
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.87
dbscSNV1_RF	Benign	0.49
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.86		Position offset: 43

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555762222; hg19: chr19-11105680;