rs17001075

chr19-10994917-A-Gchr19-10994917-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001387283.1(SMARCA4):c.1509A>G(p.Ala503=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,614,068 control chromosomes in the GnomAD database, including 1,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (102 hom., cov: 31)
  • Exomes 𝑓: 0.037 (1278 hom.)
• Consequence: SMARCA4 NM_001387283.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.98

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=-0.58).
• BP6: Variant 19-10994917-A-G is Benign according to our data. Variant chr19-10994917-A-G is described in ClinVar as [Benign]. Clinvar id is 126358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10994917-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.98 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.029 (4422/152330) while in subpopulation NFE AF= 0.041 (2788/68024). AF 95% confidence interval is 0.0397. There are 102 homozygotes in gnomad4. There are 1959 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 4417 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.1509A>G	p.Ala503=	synonymous_variant	9/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.1509A>G	p.Ala503=	synonymous_variant	9/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1509A>G	p.Ala503=	synonymous_variant	9/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.1509A>G	p.Ala503=	synonymous_variant	9/35	1	NM_003072.5	P4

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4417 AN: 152212 Hom.: 101 Cov.: 31

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0410

Gnomad OTH AF: 0.0321

GnomAD3 exomes AF: 0.0251 AC: 6313 AN: 251362 Hom.: 128 AF XY: 0.0254 AC XY: 3452 AN XY: 135882

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.0207

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00425

Gnomad FIN exome AF: 0.0176

Gnomad NFE exome AF: 0.0397

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0375 AC: 54775 AN: 1461738 Hom.: 1278 Cov.: 32 AF XY: 0.0366 AC XY: 26625 AN XY: 727170

Gnomad4 AFR exome AF: 0.0209

Gnomad4 AMR exome AF: 0.0177

Gnomad4 ASJ exome AF: 0.0196

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00457

Gnomad4 FIN exome AF: 0.0179

Gnomad4 NFE exome AF: 0.0442

Gnomad4 OTH exome AF: 0.0358

GnomAD4 genome AF: 0.0290 AC: 4422 AN: 152330 Hom.: 102 Cov.: 31 AF XY: 0.0263 AC XY: 1959 AN XY: 74490

Gnomad4 AFR AF: 0.0220

Gnomad4 AMR AF: 0.0244

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.0163

Gnomad4 NFE AF: 0.0410

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0363 Hom.: 137

Bravo AF: 0.0293

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0411

EpiControl AF: 0.0412

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2017	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 22, 2021

- -

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.34
Dann	Benign	0.70

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: rs17001075; hg19: chr19-11105593; COSMIC: COSV60792516; COSMIC: COSV60792516;