21-39243062-A-G

Variant names:

• chr21-39243062-A-G
• rs2150414
• NM_033656.4:c.2482-4489T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033656.4(BRWD1):​c.2482-4489T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 151,952 control chromosomes in the GnomAD database, including 21,057 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.52 (21057 hom., cov: 31)
• Consequence: BRWD1 NM_033656.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.339
• Publications: 15 publications found

Genes affected

BRWD1 (HGNC:12760): (bromodomain and WD repeat domain containing 1) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD) residues which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes including cell cycle progression, signal transduction, apoptosis, and gene regulation. This protein contains 2 bromodomains and multiple WD repeats. This gene is located within the Down syndrome region-2 on chromosome 21. Alternative splicing of this gene generates multiple transcript variants encoding distinct isoforms. In mouse, this gene encodes a nuclear protein that has a polyglutamine-containing region that functions as a transcriptional activation domain which may regulate chromatin remodelling and associates with a component of the SWI/SNF chromatin remodelling complex.[provided by RefSeq, Jun 2011]

BRWD1 Gene-Disease associations (from GenCC):

• agammaglobulinemia

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• ciliary dyskinesia, primary, 51

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000297893 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRWD1	NM_033656.4	c.2482-4489T>C		intron_variant	Intron 21 of 40	ENST00000342449.8	NP_387505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRWD1	ENST00000342449.8	c.2482-4489T>C		intron_variant	Intron 21 of 40	1	NM_033656.4	ENSP00000344333.3

Frequencies

GnomAD3 genomes AF: 0.520 AC: 78879 AN: 151832 Hom.: 21019 Cov.: 31

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.548

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.524

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.520 AC: 78972 AN: 151952 Hom.: 21057 Cov.: 31 AF XY: 0.528 AC XY: 39200 AN XY: 74262

African (AFR) AF: 0.632 AC: 26189 AN: 41448

American (AMR) AF: 0.549 AC: 8390 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1601 AN: 3470

East Asian (EAS) AF: 0.429 AC: 2214 AN: 5158

South Asian (SAS) AF: 0.508 AC: 2448 AN: 4816

European-Finnish (FIN) AF: 0.587 AC: 6188 AN: 10542

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.446 AC: 30288 AN: 67936

Other (OTH) AF: 0.523 AC: 1101 AN: 2104

Alfa AF: 0.511 Hom.: 4440

Bravo AF: 0.520

Asia WGS AF: 0.486 AC: 1694 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.2
DANN	Benign	0.74
PhyloP100		0.34
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: rs2150414; hg19: chr21-40614988;