rs17001073

chr19-10991317-G-Achr19-10991317-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001387283.1(SMARCA4):c.1413G>A(p.Lys471=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0375 in 1,597,060 control chromosomes in the GnomAD database, including 1,410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (126 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1284 hom.)
• Consequence: SMARCA4 NM_001387283.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.27

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=-0.35).
• BP6: Variant 19-10991317-G-A is Benign according to our data. Variant chr19-10991317-G-A is described in ClinVar as [Benign]. Clinvar id is 126356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10991317-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.27 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0329 (5015/152374) while in subpopulation NFE AF= 0.041 (2787/68040). AF 95% confidence interval is 0.0397. There are 126 homozygotes in gnomad4. There are 2252 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 5006 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.1413G>A	p.Lys471=	synonymous_variant	8/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.1413G>A	p.Lys471=	synonymous_variant	8/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1413G>A	p.Lys471=	synonymous_variant	8/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.1413G>A	p.Lys471=	synonymous_variant	8/35	1	NM_003072.5	P4

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 5006 AN: 152256 Hom.: 125 Cov.: 33

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0410

Gnomad OTH AF: 0.0387

GnomAD3 exomes AF: 0.0257 AC: 5535 AN: 214992 Hom.: 114 AF XY: 0.0256 AC XY: 2982 AN XY: 116356

Gnomad AFR exome AF: 0.0334

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.000126

Gnomad SAS exome AF: 0.00440

Gnomad FIN exome AF: 0.0174

Gnomad NFE exome AF: 0.0401

Gnomad OTH exome AF: 0.0258

GnomAD4 exome AF: 0.0380 AC: 54911 AN: 1444686 Hom.: 1284 Cov.: 33 AF XY: 0.0370 AC XY: 26565 AN XY: 717066

Gnomad4 AFR exome AF: 0.0346

Gnomad4 AMR exome AF: 0.0185

Gnomad4 ASJ exome AF: 0.0195

Gnomad4 EAS exome AF: 0.0000770

Gnomad4 SAS exome AF: 0.00459

Gnomad4 FIN exome AF: 0.0179

Gnomad4 NFE exome AF: 0.0442

Gnomad4 OTH exome AF: 0.0370

GnomAD4 genome AF: 0.0329 AC: 5015 AN: 152374 Hom.: 126 Cov.: 33 AF XY: 0.0302 AC XY: 2252 AN XY: 74506

Gnomad4 AFR AF: 0.0350

Gnomad4 AMR AF: 0.0267

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.0165

Gnomad4 NFE AF: 0.0410

Gnomad4 OTH AF: 0.0383

Alfa AF: 0.0371 Hom.: 150

Bravo AF: 0.0340

Asia WGS AF: 0.00491 AC: 17 AN: 3478

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 29, 2016	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	-0.35
Cadd	Benign	7.1
Dann	Benign	0.61
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: rs17001073; hg19: chr19-11101993; COSMIC: COSV60789992; COSMIC: COSV60789992;