rs117611401

Positions:

• chr19-11012946-C-A
• chr19-11012946-C-G
• chr19-11012946-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

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:1 B:17
• Conservation: PhyloP100: 1.96

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• 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=6, Uncertain_significance=1, Benign=7}. 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/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2275-3C>A		splice_region_variant, intron_variant		ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2275-3C>A		splice_region_variant, intron_variant		ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2275-3C>A		splice_region_variant, intron_variant			NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2275-3C>A		splice_region_variant, intron_variant		1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2275-3C>A		splice_region_variant, intron_variant				ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2275-3C>A		splice_region_variant, intron_variant		5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2275-3C>A		splice_region_variant, intron_variant				ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2275-3C>A		splice_region_variant, intron_variant				ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2275-3C>A		splice_region_variant, intron_variant		5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1687-3C>A		splice_region_variant, intron_variant				ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.919-3C>A		splice_region_variant, intron_variant				ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1000-3C>A		splice_region_variant, intron_variant				ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.760-3C>A		splice_region_variant, intron_variant				ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.628-3C>A		splice_region_variant, intron_variant				ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 369 AN: 152138 Hom.: 3 Cov.: 32

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.: 2 AF XY: 0.00272 AC XY: 369 AN XY: 135906

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.: 16 Cov.: 31 AF XY: 0.00342 AC XY: 2486 AN XY: 727220

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.: 3 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74452

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.: 2

Bravo AF: 0.00272

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00622

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:17

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:8

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2020	This variant is associated with the following publications: (PMID: 28873162) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SMARCA4: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 09, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 22, 2016	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 31, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 20, 2015	- -

Rhabdoid tumor predisposition syndrome 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 23, 2018	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. -

Intellectual disability, autosomal dominant 16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Coffin-Siris syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.44
CADD	Benign	21
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

Other links and lift over

dbSNP: rs117611401; hg19: chr19-11123622; COSMIC: COSV104418555; COSMIC: COSV104418555;