19-11012946-C-G

Variant names:

• chr19-11012946-C-G
• rs117611401
• NM_001387283.1:c.2275-3C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003072.5(SMARCA4):​c.2275-3C>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. 3/3 splice prediction tools predicting alterations to 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: 0.9996
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.96

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]

ENSG00000266936 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2275-3C>G		splice_region_variant, intron_variant	Intron 15 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2275-3C>G		splice_region_variant, intron_variant	Intron 15 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2275-3C>G		splice_region_variant, intron_variant	Intron 15 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2275-3C>G		splice_region_variant, intron_variant	Intron 15 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2275-3C>G		splice_region_variant, intron_variant	Intron 15 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2275-3C>G		splice_region_variant, intron_variant	Intron 16 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2275-3C>G		splice_region_variant, intron_variant	Intron 15 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2275-3C>G		splice_region_variant, intron_variant	Intron 15 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2275-3C>G		splice_region_variant, intron_variant	Intron 16 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1687-3C>G		splice_region_variant, intron_variant	Intron 12 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.919-3C>G		splice_region_variant, intron_variant	Intron 8 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1000-3C>G		splice_region_variant, intron_variant	Intron 8 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.760-3C>G		splice_region_variant, intron_variant	Intron 7 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.628-3C>G		splice_region_variant, intron_variant	Intron 6 of 24			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Oct 30, 2022

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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change falls in intron 15 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. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 820932). -

not provided Uncertain:1

Jan 02, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2275-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 15 in the SMARCA4 gene. This nucleotide position is well conserved in available vertebrate species. This variant has been detected in multiple individuals with no reported features of Coffin-Siris syndrome (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the supporting evidence, the association of this alteration with rhabdoid tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: -26
DS_AL_spliceai		0.81		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs117611401; hg19: chr19-11123622;