chr21-39197853-G-A

Variant names:

• chr21-39197853-G-A
• rs2150410
• NM_033656.4:c.5654-438C>T

Variant summary

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

The NM_033656.4(BRWD1):​c.5654-438C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.927 in 152,274 control chromosomes in the GnomAD database, including 65,763 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 (65763 hom., cov: 31)
• Consequence: BRWD1 NM_033656.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.689
• 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

ENSG00000297893 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• 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.5654-438C>T		intron	N/A	NP_387505.1
	BRWD1	NM_018963.5		c.5654-438C>T		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.5654-438C>T		intron	N/A	ENSP00000344333.3
	BRWD1	ENST00000333229.6	TSL:1	c.5654-438C>T		intron	N/A	ENSP00000330753.2
	BRWD1	ENST00000380800.7	TSL:1	c.5654-438C>T		intron	N/A	ENSP00000370178.3

Frequencies

GnomAD3 genomes AF: 0.927 AC: 141033 AN: 152156 Hom.: 65710 Cov.: 31

Gnomad AFR AF: 0.968

Gnomad AMI AF: 0.929

Gnomad AMR AF: 0.926

Gnomad ASJ AF: 0.964

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.930

Gnomad MID AF: 0.953

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.923

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

GnomAD4 genome AF: 0.927 AC: 141145 AN: 152274 Hom.: 65763 Cov.: 31 AF XY: 0.924 AC XY: 68777 AN XY: 74470

African (AFR) AF: 0.968 AC: 40245 AN: 41560

American (AMR) AF: 0.926 AC: 14161 AN: 15296

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

East Asian (EAS) AF: 0.603 AC: 3124 AN: 5178

South Asian (SAS) AF: 0.827 AC: 3993 AN: 4826

European-Finnish (FIN) AF: 0.930 AC: 9864 AN: 10604

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

European-Non Finnish (NFE) AF: 0.931 AC: 63336 AN: 68016

Other (OTH) AF: 0.921 AC: 1948 AN: 2116

Alfa AF: 0.924 Hom.: 200155

Bravo AF: 0.929

Asia WGS AF: 0.739 AC: 2572 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.52
DANN	Benign	0.19
PhyloP100		-0.69
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: rs2150410; hg19: chr21-40569779;