21-39270263-C-T

Variant names:

• chr21-39270263-C-T
• rs6517532
• NM_033656.4:c.1395+20G>A

Variant summary

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

The NM_033656.4(BRWD1):​c.1395+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.919 in 1,520,188 control chromosomes in the GnomAD database, including 645,784 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 0.93 (65640 hom., cov: 32)
  • Exomes 𝑓: 0.92 (580144 hom.)
• Consequence: BRWD1 NM_033656.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.92
• Publications: 12 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.96 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.1395+20G>A		intron	N/A	NP_387505.1
	BRWD1	NM_018963.5		c.1395+20G>A		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.1395+20G>A		intron	N/A	ENSP00000344333.3
	BRWD1	ENST00000333229.6	TSL:1	c.1395+20G>A		intron	N/A	ENSP00000330753.2
	BRWD1	ENST00000380800.7	TSL:1	c.1395+20G>A		intron	N/A	ENSP00000370178.3

Frequencies

GnomAD3 genomes AF: 0.926 AC: 140910 AN: 152186 Hom.: 65587 Cov.: 32

Gnomad AFR AF: 0.968

Gnomad AMI AF: 0.929

Gnomad AMR AF: 0.924

Gnomad ASJ AF: 0.964

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.924

Gnomad MID AF: 0.953

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.922

GnomAD2 exomes AF: 0.897 AC: 178522 AN: 199064 AF XY: 0.895

Gnomad AFR exome AF: 0.969

Gnomad AMR exome AF: 0.918

Gnomad ASJ exome AF: 0.967

Gnomad EAS exome AF: 0.605

Gnomad FIN exome AF: 0.923

Gnomad NFE exome AF: 0.930

Gnomad OTH exome AF: 0.916

GnomAD4 exome AF: 0.918 AC: 1256392 AN: 1367884 Hom.: 580144 Cov.: 29 AF XY: 0.917 AC XY: 618589 AN XY: 674776

African (AFR) AF: 0.969 AC: 28753 AN: 29666

American (AMR) AF: 0.922 AC: 26559 AN: 28814

Ashkenazi Jewish (ASJ) AF: 0.967 AC: 22027 AN: 22784

East Asian (EAS) AF: 0.573 AC: 21226 AN: 37050

South Asian (SAS) AF: 0.838 AC: 58673 AN: 70032

European-Finnish (FIN) AF: 0.924 AC: 47441 AN: 51346

Middle Eastern (MID) AF: 0.951 AC: 5019 AN: 5276

European-Non Finnish (NFE) AF: 0.933 AC: 995655 AN: 1066834

Other (OTH) AF: 0.910 AC: 51039 AN: 56082

GnomAD4 genome AF: 0.926 AC: 141022 AN: 152304 Hom.: 65640 Cov.: 32 AF XY: 0.922 AC XY: 68675 AN XY: 74458

African (AFR) AF: 0.968 AC: 40257 AN: 41582

American (AMR) AF: 0.924 AC: 14130 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.964 AC: 3346 AN: 3472

East Asian (EAS) AF: 0.604 AC: 3128 AN: 5182

South Asian (SAS) AF: 0.827 AC: 3995 AN: 4830

European-Finnish (FIN) AF: 0.924 AC: 9788 AN: 10590

Middle Eastern (MID) AF: 0.956 AC: 281 AN: 294

European-Non Finnish (NFE) AF: 0.931 AC: 63304 AN: 68030

Other (OTH) AF: 0.920 AC: 1946 AN: 2116

Alfa AF: 0.936 Hom.: 25403

Bravo AF: 0.928

Asia WGS AF: 0.740 AC: 2574 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.0030
DANN	Benign	0.36
PhyloP100		-1.9
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: rs6517532; hg19: chr21-40642189; COSMIC: COSV60902518;