19-11058838-C-T

Variant names:

• chr19-11058838-C-T
• rs9105
• NM_001387283.1:c.4680C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003072.5(SMARCA4):​c.4584C>T​(p.Asp1528Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.051 in 1,614,024 control chromosomes in the GnomAD database, including 2,397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (155 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2242 hom.)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.742

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 19-11058838-C-T is Benign according to our data. Variant chr19-11058838-C-T is described in ClinVar as [Benign]. Clinvar id is 126364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.742 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4680C>T	p.Asp1560Asp	synonymous_variant	Exon 33 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4584C>T	p.Asp1528Asp	synonymous_variant	Exon 32 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4680C>T	p.Asp1560Asp	synonymous_variant	Exon 33 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4584C>T	p.Asp1528Asp	synonymous_variant	Exon 32 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4590C>T	p.Asp1530Asp	synonymous_variant	Exon 32 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4494C>T	p.Asp1498Asp	synonymous_variant	Exon 32 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4494C>T	p.Asp1498Asp	synonymous_variant	Exon 31 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4494C>T	p.Asp1498Asp	synonymous_variant	Exon 31 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4491C>T	p.Asp1497Asp	synonymous_variant	Exon 32 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4005C>T	p.Asp1335Asp	synonymous_variant	Exon 29 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3234C>T	p.Asp1078Asp	synonymous_variant	Exon 25 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3216C>T	p.Asp1072Asp	synonymous_variant	Exon 24 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3078C>T	p.Asp1026Asp	synonymous_variant	Exon 24 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2895+475C>T		intron_variant	Intron 22 of 24			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.699+475C>T		intron_variant	Intron 5 of 7	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5934 AN: 152154 Hom.: 155 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.0570

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0584

Gnomad OTH AF: 0.0354

GnomAD3 exomes AF: 0.0399 AC: 10026 AN: 251378 Hom.: 271 AF XY: 0.0410 AC XY: 5566 AN XY: 135896

Gnomad AFR exome AF: 0.00948

Gnomad AMR exome AF: 0.0237

Gnomad ASJ exome AF: 0.0354

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0290

Gnomad FIN exome AF: 0.0546

Gnomad NFE exome AF: 0.0559

Gnomad OTH exome AF: 0.0439

GnomAD4 exome AF: 0.0523 AC: 76412 AN: 1461752 Hom.: 2242 Cov.: 31 AF XY: 0.0518 AC XY: 37638 AN XY: 727176

Gnomad4 AFR exome AF: 0.00789

Gnomad4 AMR exome AF: 0.0243

Gnomad4 ASJ exome AF: 0.0350

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0303

Gnomad4 FIN exome AF: 0.0537

Gnomad4 NFE exome AF: 0.0592

Gnomad4 OTH exome AF: 0.0435

GnomAD4 genome AF: 0.0389 AC: 5928 AN: 152272 Hom.: 155 Cov.: 32 AF XY: 0.0388 AC XY: 2889 AN XY: 74454

Gnomad4 AFR AF: 0.0100

Gnomad4 AMR AF: 0.0346

Gnomad4 ASJ AF: 0.0360

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0301

Gnomad4 FIN AF: 0.0570

Gnomad4 NFE AF: 0.0583

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0495 Hom.: 111

Bravo AF: 0.0359

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.0537

EpiControl AF: 0.0521

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Dec 18, 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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

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

- -

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16;C5935610:Otosclerosis 12 Benign:1

May 25, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

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 20, 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	-0.34
CADD	Benign	10
DANN	Benign	0.72
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

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: rs9105; hg19: chr19-11169514; COSMIC: COSV60787659; COSMIC: COSV60787659;