rs28997582

chr19-11035015-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001387283.1(SMARCA4):c.4053C>T(p.Asp1351=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 1,611,880 control chromosomes in the GnomAD database, including 3,655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (240 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3415 hom.)
• Consequence: SMARCA4 NM_001387283.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.33

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 19-11035015-C-T is Benign according to our data. Variant chr19-11035015-C-T is described in ClinVar as [Benign]. Clinvar id is 126362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.4053C>T	p.Asp1351=	synonymous_variant	29/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.4053C>T	p.Asp1351=	synonymous_variant	29/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4053C>T	p.Asp1351=	synonymous_variant	29/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.4053C>T	p.Asp1351=	synonymous_variant	29/35	1	NM_003072.5	P4

Frequencies

GnomAD3 genomes AF: 0.0483 AC: 7347 AN: 152126 Hom.: 240 Cov.: 33

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0701

Gnomad EAS AF: 0.0339

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0922

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0626

Gnomad OTH AF: 0.0565

GnomAD3 exomes AF: 0.0608 AC: 14942 AN: 245954 Hom.: 569 AF XY: 0.0646 AC XY: 8631 AN XY: 133706

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.0297

Gnomad ASJ exome AF: 0.0672

Gnomad EAS exome AF: 0.0340

Gnomad SAS exome AF: 0.103

Gnomad FIN exome AF: 0.0869

Gnomad NFE exome AF: 0.0643

Gnomad OTH exome AF: 0.0685

GnomAD4 exome AF: 0.0647 AC: 94438 AN: 1459636 Hom.: 3415 Cov.: 33 AF XY: 0.0660 AC XY: 47934 AN XY: 726024

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.0318

Gnomad4 ASJ exome AF: 0.0667

Gnomad4 EAS exome AF: 0.0262

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.0882

Gnomad4 NFE exome AF: 0.0650

Gnomad4 OTH exome AF: 0.0634

GnomAD4 genome AF: 0.0483 AC: 7355 AN: 152244 Hom.: 240 Cov.: 33 AF XY: 0.0504 AC XY: 3753 AN XY: 74444

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.0335

Gnomad4 ASJ AF: 0.0701

Gnomad4 EAS AF: 0.0342

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0922

Gnomad4 NFE AF: 0.0626

Gnomad4 OTH AF: 0.0582

Alfa AF: 0.0596 Hom.: 355

Bravo AF: 0.0418

Asia WGS AF: 0.0840 AC: 292 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Intellectual disability, autosomal dominant 16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Coffin-Siris syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2015

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.045
Dann	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs28997582; hg19: chr19-11145691; COSMIC: COSV60798637; COSMIC: COSV60798637;