21-39188752-T-G

Variant names:

• chr21-39188752-T-G
• rs9981595
• NM_033656.4:c.*7507A>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.*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
• Publications: 10 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033656.4. 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
	BRWD1	NM_033656.4	MANE Select	c.*7507A>C		3_prime_UTR	Exon 41 of 41	NP_387505.1
	BRWD1	NM_018963.5		c.6572-1335A>C		intron	N/A	NP_061836.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRWD1	ENST00000342449.8	TSL:1 MANE Select	c.*7507A>C		3_prime_UTR	Exon 41 of 41	ENSP00000344333.3
	BRWD1	ENST00000333229.6	TSL:1	c.6572-1335A>C		intron	N/A	ENSP00000330753.2
	BRWD1	ENST00000446924.5	TSL:2	n.*2896-1335A>C		intron	N/A	ENSP00000391014.1

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

African (AFR) AF: 0.0201 AC: 318 AN: 15786

American (AMR) AF: 0.157 AC: 154 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 710 AN: 5152

East Asian (EAS) AF: 0.147 AC: 535 AN: 3630

South Asian (SAS) AF: 0.107 AC: 1765 AN: 16458

European-Finnish (FIN) AF: 0.156 AC: 43 AN: 276

Middle Eastern (MID) AF: 0.111 AC: 180 AN: 1620

European-Non Finnish (NFE) AF: 0.132 AC: 100806 AN: 761858

Other (OTH) AF: 0.130 AC: 3540 AN: 27298

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

African (AFR) AF: 0.0322 AC: 1340 AN: 41560

American (AMR) AF: 0.115 AC: 1759 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 478 AN: 3470

East Asian (EAS) AF: 0.142 AC: 736 AN: 5184

South Asian (SAS) AF: 0.120 AC: 578 AN: 4826

European-Finnish (FIN) AF: 0.132 AC: 1398 AN: 10592

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.131 AC: 8919 AN: 67980

Other (OTH) AF: 0.0972 AC: 205 AN: 2110

Alfa AF: 0.120 Hom.: 3174

Bravo AF: 0.0998

Asia WGS AF: 0.115 AC: 400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.33
DANN	Benign	0.66
PhyloP100		-0.57
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: rs9981595; hg19: chr21-40560678;