rs141461778

Variant names:

• chr19-10987010-T-A
• rs141461778
• NM_001387283.1:c.859+7T>A

Your query was ambiguous. Multiple possible variants found:

• chr19-10987010-T-A
• chr19-10987010-T-C

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.859+7T>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 0.00208 in 1,595,254 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (24 hom.)
• Consequence: SMARCA4 NM_003072.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001071
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.67

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-10987010-T-A is Benign according to our data. Variant chr19-10987010-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 221046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10987010-T-A is described in Lovd as [Benign]. Variant chr19-10987010-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00178 (271/152246) while in subpopulation SAS AF= 0.0135 (65/4830). AF 95% confidence interval is 0.0108. There are 3 homozygotes in gnomad4. There are 134 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 271 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.859+7T>A		splice_region_variant, intron_variant	Intron 5 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.859+7T>A		splice_region_variant, intron_variant	Intron 5 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.859+7T>A		splice_region_variant, intron_variant	Intron 5 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.859+7T>A		splice_region_variant, intron_variant	Intron 5 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.859+7T>A		splice_region_variant, intron_variant	Intron 5 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.859+7T>A		splice_region_variant, intron_variant	Intron 6 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.859+7T>A		splice_region_variant, intron_variant	Intron 5 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.859+7T>A		splice_region_variant, intron_variant	Intron 5 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.859+7T>A		splice_region_variant, intron_variant	Intron 6 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.271+7T>A		splice_region_variant, intron_variant	Intron 2 of 31			ENSP00000496004.1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152128 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00370 AC: 891 AN: 240966 Hom.: 5 AF XY: 0.00449 AC XY: 589 AN XY: 131252

Gnomad AFR exome AF: 0.0000633

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.0294

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0139

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.000886

Gnomad OTH exome AF: 0.00417

GnomAD4 exome AF: 0.00211 AC: 3045 AN: 1443008 Hom.: 24 Cov.: 30 AF XY: 0.00260 AC XY: 1868 AN XY: 718690

Gnomad4 AFR exome AF: 0.000360

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.0277

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.000116

Gnomad4 NFE exome AF: 0.000705

Gnomad4 OTH exome AF: 0.00350

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152246 Hom.: 3 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74434

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00503 Hom.: 2

Bravo AF: 0.00161

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00125

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Dec 20, 2017

GeneDx

Significance: Likely 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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 27, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMARCA4: BP4, BS1, BS2 -

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

- -

Hereditary cancer-predisposing syndrome Benign:1

Sep 06, 2015

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. -

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	-0.90
CADD	Benign	0.49
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0060
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: rs141461778; hg19: chr19-11097686; COSMIC: COSV60791609; COSMIC: COSV60791609;