rs117611401

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_003072.5(SMARCA4):c.2275-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,614,076 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 16 hom. )

Consequence

SMARCA4
NM_003072.5 splice_region, intron

Scores

Splicing: ADA: 0.9875

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:17

Conservation

PhyloP100: 1.96

Variant links:

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 links:

ENSG00000266936 (HGNC:):

ENSG00000266936 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BP6

Variant 19-11012946-C-A is Benign according to our data. Variant chr19-11012946-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212240.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=6, Uncertain_significance=1}. Variant chr19-11012946-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00242 (369/152256) while in subpopulation NFE AF= 0.00388 (264/68028). AF 95% confidence interval is 0.0035. There are 3 homozygotes in gnomad4. There are 170 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 369 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.2275-3C>A		splice_region_variant, intron_variant	Intron 15 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.2275-3C>A		splice_region_variant, intron_variant	Intron 15 of 34	ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 link	c.2275-3C>A	splice_region_variant, intron_variant	Intron 15 of 35		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.2275-3C>A	splice_region_variant, intron_variant	Intron 15 of 34	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.2275-3C>A	splice_region_variant, intron_variant	Intron 15 of 34			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.2275-3C>A	splice_region_variant, intron_variant	Intron 16 of 34	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.2275-3C>A	splice_region_variant, intron_variant	Intron 15 of 33			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.2275-3C>A	splice_region_variant, intron_variant	Intron 15 of 33			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.2275-3C>A	splice_region_variant, intron_variant	Intron 16 of 34	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.1687-3C>A	splice_region_variant, intron_variant	Intron 12 of 31			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 link	c.919-3C>A	splice_region_variant, intron_variant	Intron 8 of 27			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 link	c.1000-3C>A	splice_region_variant, intron_variant	Intron 8 of 26			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 link	c.760-3C>A	splice_region_variant, intron_variant	Intron 7 of 26			ENSP00000495355.1	A0A2R8Y6N0
SMARCA4	ENST00000643857.1 link	c.628-3C>A	splice_region_variant, intron_variant	Intron 6 of 24			ENSP00000494159.1	A0A2R8Y526

Frequencies

GnomAD3 genomes

AF:

0.00243

AC:

369

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00388

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00259

AC:

650

AN:

251442

Hom.:

AF XY:

0.00272

AC XY:

369

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.00441

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00346

AC:

5057

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00342

AC XY:

2486

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000716

Gnomad4 ASJ exome

AF:

0.00333

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00159

Gnomad4 FIN exome

AF:

0.00135

Gnomad4 NFE exome

AF:

0.00401

Gnomad4 OTH exome

AF:

0.00328

GnomAD4 genome

AF:

0.00242

AC:

369

AN:

152256

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

170

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00388

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00269

Hom.:

Bravo

AF:

0.00272

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00562

EpiControl

AF:

0.00622

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:17

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:8

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMARCA4: BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 22, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28873162) -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:3

Mar 31, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Nov 23, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Jul 21, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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

- -

Coffin-Siris syndrome

Benign:1

Jan 12, 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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.84

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.34

Position offset: -26

DS_AL_spliceai

0.42

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over