chr21-39196667-T-A

Variant names:

• chr21-39196667-T-A
• NM_033656.4:c.6402A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033656.4(BRWD1):​c.6402A>T​(p.Glu2134Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRWD1 NM_033656.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0780
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000297893 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085185796).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRWD1	NM_033656.4	MANE Select	c.6402A>T	p.Glu2134Asp	missense	Exon 41 of 41	NP_387505.1	Q9NSI6-2
	BRWD1	NM_018963.5		c.6402A>T	p.Glu2134Asp	missense	Exon 41 of 42	NP_061836.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRWD1	ENST00000342449.8	TSL:1 MANE Select	c.6402A>T	p.Glu2134Asp	missense	Exon 41 of 41	ENSP00000344333.3	Q9NSI6-2
	BRWD1	ENST00000333229.6	TSL:1	c.6402A>T	p.Glu2134Asp	missense	Exon 41 of 42	ENSP00000330753.2	Q9NSI6-1
	BRWD1	ENST00000380800.7	TSL:1	c.6402A>T	p.Glu2134Asp	missense	Exon 41 of 42	ENSP00000370178.3	Q9NSI6-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.078
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.091
Sift	Uncertain	0.017	D
Sift4G	Benign	0.23	T
Polyphen		0.012	B
Vest4		0.11
MutPred		0.11		Loss of ubiquitination at K2129 (P = 0.1881)
MVP		0.57
MPC		0.070
ClinPred		0.25	T
GERP RS		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.059
gMVP		0.017
Mutation Taster		=96/4	polymorphism

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

hg19: chr21-40568593;