rs7275

Variant names:

• chr19-11060163-T-C
• rs7275
• NM_001387283.1:c.4983T>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.4887T>C​(p.Asp1629Asp) 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 NM_003072.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.51

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=-0.72).
• 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 rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4983T>C	p.Asp1661Asp	synonymous_variant	Exon 35 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4887T>C	p.Asp1629Asp	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.4983T>C	p.Asp1661Asp	synonymous_variant	Exon 35 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4887T>C	p.Asp1629Asp	synonymous_variant	Exon 34 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4893T>C	p.Asp1631Asp	synonymous_variant	Exon 34 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4797T>C	p.Asp1599Asp	synonymous_variant	Exon 34 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4797T>C	p.Asp1599Asp	synonymous_variant	Exon 33 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4797T>C	p.Asp1599Asp	synonymous_variant	Exon 33 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4794T>C	p.Asp1598Asp	synonymous_variant	Exon 34 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4308T>C	p.Asp1436Asp	synonymous_variant	Exon 31 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3537T>C	p.Asp1179Asp	synonymous_variant	Exon 27 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3519T>C	p.Asp1173Asp	synonymous_variant	Exon 26 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3381T>C	p.Asp1127Asp	synonymous_variant	Exon 26 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3147T>C	p.Asp1049Asp	synonymous_variant	Exon 24 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.951T>C	p.Asp317Asp	synonymous_variant	Exon 7 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42769 AN: 152018 Hom.: 6231 Cov.: 33

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

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.: 38 AF XY: 0.299 AC XY: 206524 AN XY: 690000

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.: 33 AF XY: 0.276 AC XY: 20553 AN XY: 74386

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

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Intellectual disability, autosomal dominant 16 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Coffin-Siris syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 19, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Other links and lift over

dbSNP: rs7275; hg19: chr19-11170839; COSMIC: COSV60786038; COSMIC: COSV60786038;