chr19-11013083-T-C

Variant names:

• chr19-11013083-T-C
• rs199634608
• NM_001387283.1:c.2409T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_003072.5(SMARCA4):​c.2409T>C​(p.Asn803Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.34
• Publications: 0 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

ENSG00000266936 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 19-11013083-T-C is Benign according to our data. Variant chr19-11013083-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000112 (17/152196) while in subpopulation AMR AF = 0.000131 (2/15270). AF 95% confidence interval is 0.0000584. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2409T>C	p.Asn803Asn	synonymous	Exon 16 of 36	NP_001374212.1	Q9HBD4
	SMARCA4	NM_003072.5	MANE Select	c.2409T>C	p.Asn803Asn	synonymous	Exon 16 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.2409T>C	p.Asn803Asn	synonymous	Exon 16 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.2409T>C	p.Asn803Asn	synonymous	Exon 16 of 36	ENSP00000495368.1	Q9HBD4
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.2409T>C	p.Asn803Asn	synonymous	Exon 16 of 35	ENSP00000343896.4	P51532-1
	SMARCA4	ENST00000643549.1		c.2409T>C	p.Asn803Asn	synonymous	Exon 16 of 35	ENSP00000493975.1	A0A2R8Y4P4

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000159 AC: 40 AN: 251310 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000313 AC: 458 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.000294 AC XY: 214 AN XY: 727238

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.000352 AC: 391 AN: 1112002

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.000131 AC: 2 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000132

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.7
DANN	Benign	0.62
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs199634608; hg19: chr19-11123759; COSMIC: COSV104654069;