19-11058838-C-T

Variant names:

• chr19-11058838-C-T
• rs9105
• NM_001387283.1:c.4680C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000344626.10(SMARCA4):​c.4584C>T​(p.Asp1528Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.051 in 1,614,024 control chromosomes in the GnomAD database, including 2,397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (155 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2242 hom.)
• Consequence: SMARCA4 ENST00000344626.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.742
• Publications: 24 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 19-11058838-C-T is Benign according to our data. Variant chr19-11058838-C-T is described in ClinVar as Benign. ClinVar VariationId is 126364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.742 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000344626.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	NM_001387283.1	MANE Plus Clinical	c.4680C>T	p.Asp1560Asp	synonymous	Exon 33 of 36	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.4584C>T	p.Asp1528Asp	synonymous	Exon 32 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.4680C>T	p.Asp1560Asp	synonymous	Exon 33 of 36	NP_001122321.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.4680C>T	p.Asp1560Asp	synonymous	Exon 33 of 36	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.4584C>T	p.Asp1528Asp	synonymous	Exon 32 of 35	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.4590C>T	p.Asp1530Asp	synonymous	Exon 32 of 35	ENSP00000493975.1

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5934 AN: 152154 Hom.: 155 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.0570

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0584

Gnomad OTH AF: 0.0354

GnomAD2 exomes AF: 0.0399 AC: 10026 AN: 251378 AF XY: 0.0410

Gnomad AFR exome AF: 0.00948

Gnomad AMR exome AF: 0.0237

Gnomad ASJ exome AF: 0.0354

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0546

Gnomad NFE exome AF: 0.0559

Gnomad OTH exome AF: 0.0439

GnomAD4 exome AF: 0.0523 AC: 76412 AN: 1461752 Hom.: 2242 Cov.: 31 AF XY: 0.0518 AC XY: 37638 AN XY: 727176

African (AFR) AF: 0.00789 AC: 264 AN: 33480

American (AMR) AF: 0.0243 AC: 1086 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0350 AC: 915 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0303 AC: 2613 AN: 86254

European-Finnish (FIN) AF: 0.0537 AC: 2864 AN: 53368

Middle Eastern (MID) AF: 0.0300 AC: 173 AN: 5768

European-Non Finnish (NFE) AF: 0.0592 AC: 65868 AN: 1111932

Other (OTH) AF: 0.0435 AC: 2629 AN: 60392

GnomAD4 genome AF: 0.0389 AC: 5928 AN: 152272 Hom.: 155 Cov.: 32 AF XY: 0.0388 AC XY: 2889 AN XY: 74454

African (AFR) AF: 0.0100 AC: 417 AN: 41578

American (AMR) AF: 0.0346 AC: 529 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5186

South Asian (SAS) AF: 0.0301 AC: 145 AN: 4824

European-Finnish (FIN) AF: 0.0570 AC: 604 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0583 AC: 3968 AN: 68012

Other (OTH) AF: 0.0350 AC: 74 AN: 2112

Alfa AF: 0.0435 Hom.: 160

Bravo AF: 0.0359

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.0537

EpiControl AF: 0.0521

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Coffin-Siris syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Intellectual disability, autosomal dominant 16 (1)
-	-	1	not provided (1)
-	-	1	Rhabdoid tumor predisposition syndrome 2 (1)
-	-	1	Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16;C5935610:Otosclerosis 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	10
DANN	Benign	0.72
PhyloP100		-0.74
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Mutation Taster		=99/1	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: rs9105; hg19: chr19-11169514; COSMIC: COSV60787659; COSMIC: COSV60787659;