19-10995004-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001387283.1(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_001387283.1 splice_region, intron

Scores

Splicing: ADA: 0.8718

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.00600

Publications

0 publications found

Variant links:

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

SMARCA4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 link	c.1593+3A>G		splice_region_variant, intron_variant	Intron 9 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.1593+3A>G		splice_region_variant, intron_variant	Intron 9 of 34	ENST00000344626.10	NP_003063.2

Ensembl

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 16, 2025

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 not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Pathogenic

(source)

DANN

Benign

0.65

PhyloP100

0.0060

PromoterAI

-0.16

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=60/40

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over