rs17001073

Variant names:

• chr19-10991317-G-A
• rs17001073
• NM_001387283.1:c.1413G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-10991317-G-A
• chr19-10991317-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001387283.1(SMARCA4):​c.1413G>A​(p.Lys471Lys) 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:9
• Conservation: PhyloP100: 2.27
• Publications: 15 publications found

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]

SMARCA4 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 126356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 126 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387283.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	NM_001387283.1	MANE Plus Clinical	c.1413G>A	p.Lys471Lys	synonymous	Exon 8 of 36	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.1413G>A	p.Lys471Lys	synonymous	Exon 8 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.1413G>A	p.Lys471Lys	synonymous	Exon 8 of 36	NP_001122321.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.1413G>A	p.Lys471Lys	synonymous	Exon 8 of 36	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.1413G>A	p.Lys471Lys	synonymous	Exon 8 of 35	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.1413G>A	p.Lys471Lys	synonymous	Exon 8 of 35	ENSP00000493975.1

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

GnomAD2 exomes AF: 0.0257 AC: 5535 AN: 214992 AF XY: 0.0256

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 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

African (AFR) AF: 0.0346 AC: 1148 AN: 33216

American (AMR) AF: 0.0185 AC: 768 AN: 41618

Ashkenazi Jewish (ASJ) AF: 0.0195 AC: 503 AN: 25816

East Asian (EAS) AF: 0.0000770 AC: 3 AN: 38940

South Asian (SAS) AF: 0.00459 AC: 385 AN: 83920

European-Finnish (FIN) AF: 0.0179 AC: 923 AN: 51674

Middle Eastern (MID) AF: 0.0213 AC: 115 AN: 5400

European-Non Finnish (NFE) AF: 0.0442 AC: 48855 AN: 1104348

Other (OTH) AF: 0.0370 AC: 2211 AN: 59754

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

African (AFR) AF: 0.0350 AC: 1457 AN: 41592

American (AMR) AF: 0.0267 AC: 409 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4834

European-Finnish (FIN) AF: 0.0165 AC: 175 AN: 10632

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0410 AC: 2787 AN: 68040

Other (OTH) AF: 0.0383 AC: 81 AN: 2114

Alfa AF: 0.0368 Hom.: 176

Bravo AF: 0.0340

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jun 29, 2016

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.

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.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 22, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

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

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

Jun 21, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	7.1
DANN	Benign	0.61
PhyloP100		2.3
PromoterAI		0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17001073; hg19: chr19-11101993; COSMIC: COSV60789992; COSMIC: COSV60789992;