rs28997582

Variant names:

• chr19-11035015-C-T
• rs28997582
• NM_001387283.1:c.4053C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BA1

The NM_003072.5(SMARCA4):​c.4053C>T​(p.Asp1351Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 1,611,880 control chromosomes in the GnomAD database, including 3,655 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (240 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3415 hom.)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.33
• Publications: 20 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: Orphanet, ClinGen, 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: G2P, Ambry Genetics, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• otosclerosis

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• 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: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP6: Variant 19-11035015-C-T is Benign according to our data. Variant chr19-11035015-C-T is described in ClinVar as Benign. ClinVar VariationId is 126362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0961 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003072.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	NM_001387283.1	MANE Plus Clinical	c.4053C>T	p.Asp1351Asp	synonymous	Exon 29 of 36	NP_001374212.1	Q9HBD4
	SMARCA4	NM_003072.5	MANE Select	c.4053C>T	p.Asp1351Asp	synonymous	Exon 29 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.4053C>T	p.Asp1351Asp	synonymous	Exon 29 of 36	NP_001122321.1	Q9HBD4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.4053C>T	p.Asp1351Asp	synonymous	Exon 29 of 36	ENSP00000495368.1	Q9HBD4
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.4053C>T	p.Asp1351Asp	synonymous	Exon 29 of 35	ENSP00000343896.4	P51532-1
	SMARCA4	ENST00000643549.1		c.3954C>T	p.Asp1318Asp	synonymous	Exon 28 of 35	ENSP00000493975.1	A0A2R8Y4P4

Frequencies

GnomAD3 genomes AF: 0.0483 AC: 7347 AN: 152126 Hom.: 240 Cov.: 33

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0701

Gnomad EAS AF: 0.0339

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0922

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0626

Gnomad OTH AF: 0.0565

GnomAD2 exomes AF: 0.0608 AC: 14942 AN: 245954 AF XY: 0.0646

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.0297

Gnomad ASJ exome AF: 0.0672

Gnomad EAS exome AF: 0.0340

Gnomad FIN exome AF: 0.0869

Gnomad NFE exome AF: 0.0643

Gnomad OTH exome AF: 0.0685

GnomAD4 exome AF: 0.0647 AC: 94438 AN: 1459636 Hom.: 3415 Cov.: 33 AF XY: 0.0660 AC XY: 47934 AN XY: 726024

African (AFR) AF: 0.0110 AC: 369 AN: 33452

American (AMR) AF: 0.0318 AC: 1419 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.0667 AC: 1741 AN: 26086

East Asian (EAS) AF: 0.0262 AC: 1041 AN: 39664

South Asian (SAS) AF: 0.102 AC: 8765 AN: 86028

European-Finnish (FIN) AF: 0.0882 AC: 4635 AN: 52522

Middle Eastern (MID) AF: 0.0666 AC: 378 AN: 5674

European-Non Finnish (NFE) AF: 0.0650 AC: 72267 AN: 1111336

Other (OTH) AF: 0.0634 AC: 3823 AN: 60298

GnomAD4 genome AF: 0.0483 AC: 7355 AN: 152244 Hom.: 240 Cov.: 33 AF XY: 0.0504 AC XY: 3753 AN XY: 74444

African (AFR) AF: 0.0129 AC: 537 AN: 41570

American (AMR) AF: 0.0335 AC: 513 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0701 AC: 243 AN: 3468

East Asian (EAS) AF: 0.0342 AC: 176 AN: 5152

South Asian (SAS) AF: 0.104 AC: 499 AN: 4818

European-Finnish (FIN) AF: 0.0922 AC: 977 AN: 10600

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0626 AC: 4259 AN: 68010

Other (OTH) AF: 0.0582 AC: 123 AN: 2112

Alfa AF: 0.0573 Hom.: 407

Bravo AF: 0.0418

Asia WGS AF: 0.0840 AC: 292 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Coffin-Siris syndrome (1)
-	-	1	Intellectual disability, autosomal dominant 16 (1)
-	-	1	not provided (1)
-	-	1	Rhabdoid tumor predisposition syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.045
DANN	Benign	0.82
PhyloP100		-2.3
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs28997582; hg19: chr19-11145691; COSMIC: COSV60798637;