rs2836978

Positions:

• chr21-39294345-T-C
• chr21-39294345-T-G
• chr21-39294345-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033656.4(BRWD1):​c.610-313A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0938 in 152,210 control chromosomes in the GnomAD database, including 814 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 0.094 (814 hom., cov: 33)
• Consequence: BRWD1 NM_033656.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.285

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRWD1	NM_033656.4	c.610-313A>G		intron_variant		ENST00000342449.8	NP_387505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRWD1	ENST00000342449.8	c.610-313A>G		intron_variant		1	NM_033656.4	ENSP00000344333	A2
BRWD1	ENST00000333229.6	c.610-313A>G		intron_variant		1		ENSP00000330753	P2
BRWD1	ENST00000380800.7	c.610-313A>G		intron_variant		1		ENSP00000370178	A2

Frequencies

GnomAD3 genomes AF: 0.0939 AC: 14280 AN: 152092 Hom.: 814 Cov.: 33

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.0924

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

GnomAD4 genome AF: 0.0938 AC: 14283 AN: 152210 Hom.: 814 Cov.: 33 AF XY: 0.0923 AC XY: 6868 AN XY: 74438

Gnomad4 AFR AF: 0.0237

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.0915

Alfa AF: 0.106 Hom.: 510

Bravo AF: 0.0938

Asia WGS AF: 0.111 AC: 386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.2
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs2836978; hg19: chr21-40666271;