rs9981595

Positions:

• chr21-39188752-T-G

Variant summary

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

The NM_033656.4(BRWD1):​c.*7507A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 985,278 control chromosomes in the GnomAD database, including 8,098 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 0.10 (918 hom., cov: 32)
  • Exomes 𝑓: 0.13 (7180 hom.)
• Consequence: BRWD1 NM_033656.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.571

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 = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRWD1	NM_033656.4	c.*7507A>C		3_prime_UTR_variant	41/41	ENST00000342449.8	NP_387505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRWD1	ENST00000342449.8	c.*7507A>C		3_prime_UTR_variant	41/41	1	NM_033656.4	ENSP00000344333	A2
BRWD1	ENST00000333229.6	c.6572-1335A>C		intron_variant		1		ENSP00000330753	P2
BRWD1	ENST00000446924.5	c.*2896-1335A>C		intron_variant, NMD_transcript_variant		2		ENSP00000391014

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15451 AN: 152098 Hom.: 916 Cov.: 32

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.0982

GnomAD4 exome AF: 0.130 AC: 108051 AN: 833062 Hom.: 7180 Cov.: 33 AF XY: 0.130 AC XY: 49920 AN XY: 384698

Gnomad4 AFR exome AF: 0.0201

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.156

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.130

GnomAD4 genome AF: 0.102 AC: 15463 AN: 152216 Hom.: 918 Cov.: 32 AF XY: 0.101 AC XY: 7535 AN XY: 74428

Gnomad4 AFR AF: 0.0322

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.0972

Alfa AF: 0.125 Hom.: 1089

Bravo AF: 0.0998

Asia WGS AF: 0.115 AC: 400 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	0.33
DANN	Benign	0.66

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: rs9981595; hg19: chr21-40560678;