19-11021615-G-A

Variant names:

• chr19-11021615-G-A
• rs564402674
• NM_001387283.1:c.2617-110G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001387283.1(SMARCA4):​c.2617-110G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,371,434 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (14 hom.)
• Consequence: SMARCA4 NM_001387283.1 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.111
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00193 (294/152316) while in subpopulation NFE AF = 0.00334 (227/68022). AF 95% confidence interval is 0.00298. There are 0 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 14 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.2617-110G>A		intron	N/A	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.2617-110G>A		intron	N/A	NP_003063.2
	SMARCA4	NM_001128849.3		c.2617-110G>A		intron	N/A	NP_001122321.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.2617-110G>A		intron	N/A	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.2617-110G>A		intron	N/A	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.2617-110G>A		intron	N/A	ENSP00000493975.1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00334

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00209 AC: 296 AN: 141710 AF XY: 0.00191

Gnomad AFR exome AF: 0.000935

Gnomad AMR exome AF: 0.00170

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000133

Gnomad NFE exome AF: 0.00388

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00367 AC: 4477 AN: 1219118 Hom.: 14 Cov.: 18 AF XY: 0.00358 AC XY: 2183 AN XY: 609694

African (AFR) AF: 0.000672 AC: 19 AN: 28258

American (AMR) AF: 0.00161 AC: 57 AN: 35490

Ashkenazi Jewish (ASJ) AF: 0.0000415 AC: 1 AN: 24098

East Asian (EAS) AF: 0.00 AC: 0 AN: 34916

South Asian (SAS) AF: 0.000839 AC: 63 AN: 75104

European-Finnish (FIN) AF: 0.000215 AC: 8 AN: 37268

Middle Eastern (MID) AF: 0.000370 AC: 2 AN: 5402

European-Non Finnish (NFE) AF: 0.00452 AC: 4183 AN: 926244

Other (OTH) AF: 0.00275 AC: 144 AN: 52338

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.00195 AC XY: 145 AN XY: 74472

African (AFR) AF: 0.000697 AC: 29 AN: 41578

American (AMR) AF: 0.00170 AC: 26 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00334 AC: 227 AN: 68022

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00251 Hom.: 1

Bravo AF: 0.00193

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.1
DANN	Benign	0.85
PhyloP100		-0.11
PromoterAI		-0.028	Neutral
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: rs564402674; hg19: chr19-11132291; COSMIC: COSV106477823;