rs7935

Positions:

• chr19-10994932-T-C

Variant summary

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

The NM_003072.5(SMARCA4):​c.1524T>C​(p.His508His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,613,226 control chromosomes in the GnomAD database, including 100,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8201 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92385 hom.)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.80

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=-0.57).
• BP6: Variant 19-10994932-T-C is Benign according to our data. Variant chr19-10994932-T-C is described in ClinVar as [Benign]. Clinvar id is 126359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10994932-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1524T>C	p.His508His	synonymous_variant	9/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1524T>C	p.His508His	synonymous_variant	9/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1524T>C	p.His508His	synonymous_variant	9/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1524T>C	p.His508His	synonymous_variant	9/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1524T>C	p.His508His	synonymous_variant	9/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1524T>C	p.His508His	synonymous_variant	10/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1524T>C	p.His508His	synonymous_variant	9/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1524T>C	p.His508His	synonymous_variant	9/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1524T>C	p.His508His	synonymous_variant	10/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.936T>C	p.His312His	synonymous_variant	6/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.168T>C	p.His56His	synonymous_variant	2/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.252T>C	p.His84His	synonymous_variant	2/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.12T>C	p.His4His	synonymous_variant	1/27			ENSP00000495355.1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49334 AN: 151958 Hom.: 8181 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.320

GnomAD3 exomes AF: 0.328 AC: 82139 AN: 250764 Hom.: 14076 AF XY: 0.339 AC XY: 45936 AN XY: 135550

Gnomad AFR exome AF: 0.302

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.340

Gnomad EAS exome AF: 0.235

Gnomad SAS exome AF: 0.436

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.351

Gnomad OTH exome AF: 0.346

GnomAD4 exome AF: 0.352 AC: 514614 AN: 1461150 Hom.: 92385 Cov.: 37 AF XY: 0.355 AC XY: 258355 AN XY: 726880

Gnomad4 AFR exome AF: 0.305

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.344

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.433

Gnomad4 FIN exome AF: 0.361

Gnomad4 NFE exome AF: 0.358

Gnomad4 OTH exome AF: 0.345

GnomAD4 genome AF: 0.325 AC: 49391 AN: 152076 Hom.: 8201 Cov.: 32 AF XY: 0.326 AC XY: 24220 AN XY: 74338

Gnomad4 AFR AF: 0.304

Gnomad4 AMR AF: 0.238

Gnomad4 ASJ AF: 0.350

Gnomad4 EAS AF: 0.244

Gnomad4 SAS AF: 0.413

Gnomad4 FIN AF: 0.368

Gnomad4 NFE AF: 0.349

Gnomad4 OTH AF: 0.321

Alfa AF: 0.346 Hom.: 21649

Bravo AF: 0.312

Asia WGS AF: 0.333 AC: 1158 AN: 3478

EpiCase AF: 0.362

EpiControl AF: 0.353

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 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	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
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	-0.57
CADD	Benign	0.065
DANN	Benign	0.39
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

Other links and lift over

dbSNP: rs7935; hg19: chr19-11105608; COSMIC: COSV60787320; COSMIC: COSV60787320;