chr19-11060163-T-C

Position:

chr19-11060163-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000344626.10(SMARCA4):c.4887T>C(p.Asp1629=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,551,084 control chromosomes in the GnomAD database, including 69,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6233 hom., cov: 33)

Exomes 𝑓: 0.30 ( 63680 hom. )

Consequence

SMARCA4
ENST00000344626.10 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -3.51

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 19-11060163-T-C is Benign according to our data. Variant chr19-11060163-T-C is described in ClinVar as [Benign]. Clinvar id is 126365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11060163-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.51 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 linkuse as main transcript	c.4983T>C	p.Asp1661=	synonymous_variant	35/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 linkuse as main transcript	c.4887T>C	p.Asp1629=	synonymous_variant	34/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2 linkuse as main transcript	c.4983T>C	p.Asp1661=	synonymous_variant	35/36		NM_001387283.1	ENSP00000495368
SMARCA4	ENST00000344626.10 linkuse as main transcript	c.4887T>C	p.Asp1629=	synonymous_variant	34/35	1	NM_003072.5	ENSP00000343896	P4	P51532-1

Frequencies

GnomAD3 genomes

AF:

0.281

AC:

42769

AN:

152018

Hom.:

6231

Cov.:

show subpopulations

Gnomad AFR

AF:

0.303

Gnomad AMI

AF:

0.344

Gnomad AMR

AF:

0.214

Gnomad ASJ

AF:

0.259

Gnomad EAS

AF:

0.0912

Gnomad SAS

AF:

0.332

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.303

Gnomad OTH

AF:

0.265

GnomAD3 exomes

AF:

0.261

AC:

40606

AN:

155306

Hom.:

5762

AF XY:

0.271

AC XY:

22221

AN XY:

81886

show subpopulations

Gnomad AFR exome

AF:

0.300

Gnomad AMR exome

AF:

0.163

Gnomad ASJ exome

AF:

0.249

Gnomad EAS exome

AF:

0.0819

Gnomad SAS exome

AF:

0.356

Gnomad FIN exome

AF:

0.231

Gnomad NFE exome

AF:

0.303

Gnomad OTH exome

AF:

0.280

GnomAD4 exome

AF:

0.297

AC:

416170

AN:

1398948

Hom.:

63680

Cov.:

AF XY:

0.299

AC XY:

206524

AN XY:

690000

show subpopulations

Gnomad4 AFR exome

AF:

0.300

Gnomad4 AMR exome

AF:

0.167

Gnomad4 ASJ exome

AF:

0.254

Gnomad4 EAS exome

AF:

0.0895

Gnomad4 SAS exome

AF:

0.347

Gnomad4 FIN exome

AF:

0.233

Gnomad4 NFE exome

AF:

0.309

Gnomad4 OTH exome

AF:

0.292

GnomAD4 genome

AF:

0.281

AC:

42797

AN:

152136

Hom.:

6233

Cov.:

AF XY:

0.276

AC XY:

20553

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.303

Gnomad4 AMR

AF:

0.213

Gnomad4 ASJ

AF:

0.259

Gnomad4 EAS

AF:

0.0912

Gnomad4 SAS

AF:

0.330

Gnomad4 FIN

AF:

0.231

Gnomad4 NFE

AF:

0.303

Gnomad4 OTH

AF:

0.264

Alfa

AF:

0.297

Hom.:

11399

Bravo

AF:

0.279

Asia WGS

AF:

0.224

AC:

782

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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 19, 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

-0.72

CADD

Benign

0.13

DANN

Benign

0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over