chr19-10994917-A-G

Variant names:

• chr19-10994917-A-G
• rs17001075
• NM_001387283.1:c.1509A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001387283.1(SMARCA4):​c.1509A>G​(p.Ala503Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,614,068 control chromosomes in the GnomAD database, including 1,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (102 hom., cov: 31)
  • Exomes 𝑓: 0.037 (1278 hom.)
• Consequence: SMARCA4 NM_001387283.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.98
• Publications: 17 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-10994917-A-G is Benign according to our data. Variant chr19-10994917-A-G is described in ClinVar as Benign. ClinVar VariationId is 126358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.98 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.029 (4422/152330) while in subpopulation NFE AF = 0.041 (2788/68024). AF 95% confidence interval is 0.0397. There are 102 homozygotes in GnomAd4. There are 1959 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 102 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387283.1. 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.1509A>G	p.Ala503Ala	synonymous	Exon 9 of 36	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.1509A>G	p.Ala503Ala	synonymous	Exon 9 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.1509A>G	p.Ala503Ala	synonymous	Exon 9 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.1509A>G	p.Ala503Ala	synonymous	Exon 9 of 36	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.1509A>G	p.Ala503Ala	synonymous	Exon 9 of 35	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.1509A>G	p.Ala503Ala	synonymous	Exon 9 of 35	ENSP00000493975.1

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4417 AN: 152212 Hom.: 101 Cov.: 31

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0410

Gnomad OTH AF: 0.0321

GnomAD2 exomes AF: 0.0251 AC: 6313 AN: 251362 AF XY: 0.0254

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.0207

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0176

Gnomad NFE exome AF: 0.0397

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0375 AC: 54775 AN: 1461738 Hom.: 1278 Cov.: 32 AF XY: 0.0366 AC XY: 26625 AN XY: 727170

African (AFR) AF: 0.0209 AC: 701 AN: 33478

American (AMR) AF: 0.0177 AC: 790 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 511 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00457 AC: 394 AN: 86256

European-Finnish (FIN) AF: 0.0179 AC: 955 AN: 53418

Middle Eastern (MID) AF: 0.0208 AC: 120 AN: 5768

European-Non Finnish (NFE) AF: 0.0442 AC: 49141 AN: 1111876

Other (OTH) AF: 0.0358 AC: 2160 AN: 60384

GnomAD4 genome AF: 0.0290 AC: 4422 AN: 152330 Hom.: 102 Cov.: 31 AF XY: 0.0263 AC XY: 1959 AN XY: 74490

African (AFR) AF: 0.0220 AC: 915 AN: 41580

American (AMR) AF: 0.0244 AC: 374 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.0163 AC: 173 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0410 AC: 2788 AN: 68024

Other (OTH) AF: 0.0317 AC: 67 AN: 2112

Alfa AF: 0.0357 Hom.: 161

Bravo AF: 0.0293

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0411

EpiControl AF: 0.0412

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Coffin-Siris syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Intellectual disability, autosomal dominant 16 (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	-0.58
CADD	Benign	0.34
DANN	Benign	0.70
PhyloP100		-4.0
PromoterAI		0.0046	Neutral
Mutation Taster		=93/7	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: rs17001075; hg19: chr19-11105593; COSMIC: COSV60792516;