rs34930626

Positions:

• chr19-11058901-G-A
• chr19-11058901-G-C
• chr19-11058901-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003072.5(SMARCA4):​c.4635+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,608,008 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (29 hom.)
• Consequence: SMARCA4 NM_003072.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.18

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-11058901-G-A is Benign according to our data. Variant chr19-11058901-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 328041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00924 (1406/152246) while in subpopulation AFR AF= 0.032 (1331/41540). AF 95% confidence interval is 0.0306. There are 20 homozygotes in gnomad4. There are 665 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1406 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4731+12G>A		intron_variant		ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4635+12G>A		intron_variant		ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4731+12G>A		intron_variant			NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4635+12G>A		intron_variant		1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4641+12G>A		intron_variant				ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4545+12G>A		intron_variant		5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4545+12G>A		intron_variant				ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4545+12G>A		intron_variant				ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4542+12G>A		intron_variant		5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4056+12G>A		intron_variant				ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3285+12G>A		intron_variant				ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3267+12G>A		intron_variant				ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3129+12G>A		intron_variant				ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2895+538G>A		intron_variant				ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.699+538G>A		intron_variant		3		ENSP00000495197.1

Frequencies

GnomAD3 genomes AF: 0.00924 AC: 1405 AN: 152128 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00241 AC: 604 AN: 250136 Hom.: 6 AF XY: 0.00170 AC XY: 230 AN XY: 135326

Gnomad AFR exome AF: 0.0339

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000981 AC: 1428 AN: 1455762 Hom.: 29 Cov.: 29 AF XY: 0.000824 AC XY: 597 AN XY: 724582

Gnomad4 AFR exome AF: 0.0362

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000325

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00924 AC: 1406 AN: 152246 Hom.: 20 Cov.: 32 AF XY: 0.00893 AC XY: 665 AN XY: 74440

Gnomad4 AFR AF: 0.0320

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00456 Hom.: 3

Bravo AF: 0.0107

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 13, 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. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.58

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: rs34930626; hg19: chr19-11169577; COSMIC: COSV104418419; COSMIC: COSV104418419;