19-11060151-C-G

Variant names:

• chr19-11060151-C-G
• rs146427223
• NM_001387283.1:c.4971C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001387283.1(SMARCA4):​c.4971C>G​(p.Val1657Val) variant causes a synonymous 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V1657V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_001387283.1 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.16
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: 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.4971C>G	p.Val1657Val	synonymous_variant	Exon 35 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4875C>G	p.Val1625Val	synonymous_variant	Exon 34 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4971C>G	p.Val1657Val	synonymous_variant	Exon 35 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4875C>G	p.Val1625Val	synonymous_variant	Exon 34 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4881C>G	p.Val1627Val	synonymous_variant	Exon 34 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4785C>G	p.Val1595Val	synonymous_variant	Exon 34 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4785C>G	p.Val1595Val	synonymous_variant	Exon 33 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4785C>G	p.Val1595Val	synonymous_variant	Exon 33 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4782C>G	p.Val1594Val	synonymous_variant	Exon 34 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4296C>G	p.Val1432Val	synonymous_variant	Exon 31 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3525C>G	p.Val1175Val	synonymous_variant	Exon 27 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3507C>G	p.Val1169Val	synonymous_variant	Exon 26 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3369C>G	p.Val1123Val	synonymous_variant	Exon 26 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3135C>G	p.Val1045Val	synonymous_variant	Exon 24 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.939C>G	p.Val313Val	synonymous_variant	Exon 7 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Nov 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 1657 of the SMARCA4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SMARCA4 protein. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	14
DANN	Benign	0.60
PhyloP100		-4.2
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.81		Position offset: 0

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

Other links and lift over

dbSNP: rs146427223; hg19: chr19-11170827;