NM_001387283.1:c.-28-2661G>A

Variant names:

• chr19-10981463-G-A
• rs11669133
• NM_001387283.1:c.-28-2661G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001387283.1(SMARCA4):​c.-28-2661G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 152,332 control chromosomes in the GnomAD database, including 168 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.041 (168 hom., cov: 32)
• Consequence: SMARCA4 NM_001387283.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.965
• Publications: 25 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.-28-2661G>A		intron_variant	Intron 1 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.-31-2658G>A		intron_variant	Intron 1 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.-28-2661G>A		intron_variant	Intron 1 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.-31-2658G>A		intron_variant	Intron 1 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.-28-2661G>A		intron_variant	Intron 1 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.-28-2661G>A		intron_variant	Intron 2 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.-31-2658G>A		intron_variant	Intron 1 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.-28-2661G>A		intron_variant	Intron 1 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.-260-2017G>A		intron_variant	Intron 1 of 34	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes AF: 0.0407 AC: 6194 AN: 152214 Hom.: 167 Cov.: 32

Gnomad AFR AF: 0.0596

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0294

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0212

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0414

Gnomad OTH AF: 0.0449

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

GnomAD4 genome AF: 0.0407 AC: 6206 AN: 152332 Hom.: 168 Cov.: 32 AF XY: 0.0380 AC XY: 2832 AN XY: 74484

African (AFR) AF: 0.0597 AC: 2483 AN: 41570

American (AMR) AF: 0.0294 AC: 449 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 89 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4824

European-Finnish (FIN) AF: 0.0212 AC: 225 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0414 AC: 2815 AN: 68032

Other (OTH) AF: 0.0445 AC: 94 AN: 2114

Alfa AF: 0.0390 Hom.: 395

Bravo AF: 0.0423

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.2
DANN	Benign	0.57
PhyloP100		0.96
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs11669133; hg19: chr19-11092139;