19-11025467-C-A

Variant names:

• chr19-11025467-C-A
• rs770014321
• NM_001387283.1:c.3127C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_001387283.1(SMARCA4):​c.3127C>A​(p.Arg1043Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1043R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.449
• Publications: 10 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: Benign. The variant received -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 19-11025467-C-A is Benign according to our data. Variant chr19-11025467-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1159756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.449 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3127C>A	p.Arg1043Arg	synonymous_variant	Exon 22 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3127C>A	p.Arg1043Arg	synonymous_variant	Exon 22 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3127C>A	p.Arg1043Arg	synonymous_variant	Exon 22 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3127C>A	p.Arg1043Arg	synonymous_variant	Exon 22 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3127C>A	p.Arg1043Arg	synonymous_variant	Exon 22 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3127C>A	p.Arg1043Arg	synonymous_variant	Exon 23 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3127C>A	p.Arg1043Arg	synonymous_variant	Exon 22 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3127C>A	p.Arg1043Arg	synonymous_variant	Exon 22 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3127C>A	p.Arg1043Arg	synonymous_variant	Exon 23 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2539C>A	p.Arg847Arg	synonymous_variant	Exon 19 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1771C>A	p.Arg591Arg	synonymous_variant	Exon 15 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1852C>A	p.Arg618Arg	synonymous_variant	Exon 15 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1612C>A	p.Arg538Arg	synonymous_variant	Exon 14 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1480C>A	p.Arg494Arg	synonymous_variant	Exon 13 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251006 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461086 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726862

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.0000569 AC: 3 AN: 52754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111896

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Benign:1

Oct 27, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Nov 14, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SMARCA4-related disorder Benign:1

Feb 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	4.4
DANN	Benign	0.75
PhyloP100		-0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs770014321; hg19: chr19-11136143;