NM_001387283.1:c.2001+279A>G

Variant names:

• chr19-11003676-A-G
• rs12983316
• NM_001387283.1:c.2001+279A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001387283.1(SMARCA4):​c.2001+279A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 151,490 control chromosomes in the GnomAD database, including 1,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.12 (1438 hom., cov: 32)
• Consequence: SMARCA4 NM_001387283.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.468
• Publications: 22 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-11003676-A-G is Benign according to our data. Variant chr19-11003676-A-G is described in ClinVar as [Benign]. Clinvar id is 1248789.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2001+279A>G		intron_variant	Intron 13 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2001+279A>G		intron_variant	Intron 13 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2001+279A>G		intron_variant	Intron 13 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2001+279A>G		intron_variant	Intron 13 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2001+279A>G		intron_variant	Intron 13 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2001+279A>G		intron_variant	Intron 14 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2001+279A>G		intron_variant	Intron 13 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2001+279A>G		intron_variant	Intron 13 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2001+279A>G		intron_variant	Intron 14 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1413+279A>G		intron_variant	Intron 10 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.645+279A>G		intron_variant	Intron 6 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.726+279A>G		intron_variant	Intron 6 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.486+279A>G		intron_variant	Intron 5 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.354+279A>G		intron_variant	Intron 4 of 24			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18599 AN: 151414 Hom.: 1437 Cov.: 32

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.0881

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.0865

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.0641

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.119

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.123 AC: 18595 AN: 151490 Hom.: 1438 Cov.: 32 AF XY: 0.126 AC XY: 9295 AN XY: 73962

African (AFR) AF: 0.0304 AC: 1255 AN: 41254

American (AMR) AF: 0.192 AC: 2912 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 408 AN: 3468

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5138

South Asian (SAS) AF: 0.0876 AC: 420 AN: 4792

European-Finnish (FIN) AF: 0.212 AC: 2206 AN: 10422

Middle Eastern (MID) AF: 0.0664 AC: 19 AN: 286

European-Non Finnish (NFE) AF: 0.163 AC: 11041 AN: 67920

Other (OTH) AF: 0.118 AC: 247 AN: 2098

Alfa AF: 0.143 Hom.: 2589

Bravo AF: 0.115

Asia WGS AF: 0.0400 AC: 139 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.7
DANN	Benign	0.70
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12983316; hg19: chr19-11114352;