rs753301336

Variant names:

• chr21-39196542-G-A
• rs753301336
• NM_033656.4:c.6527C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-39196542-G-A
• chr21-39196542-G-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.6527C>T​(p.Thr2176Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,820 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: BRWD1 NM_033656.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28
• Publications: 1 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=0.12936655).

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.6527C>T	p.Thr2176Ile	missense	Exon 41 of 41	NP_387505.1	Q9NSI6-2
	BRWD1	NM_018963.5		c.6527C>T	p.Thr2176Ile	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.6527C>T	p.Thr2176Ile	missense	Exon 41 of 41	ENSP00000344333.3	Q9NSI6-2
	BRWD1	ENST00000333229.6	TSL:1	c.6527C>T	p.Thr2176Ile	missense	Exon 41 of 42	ENSP00000330753.2	Q9NSI6-1
	BRWD1	ENST00000380800.7	TSL:1	c.6527C>T	p.Thr2176Ile	missense	Exon 41 of 42	ENSP00000370178.3	Q9NSI6-3

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151820 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250168 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151820 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74124

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41344

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67930

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

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	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.091
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.20	T
Polyphen		0.22	B
Vest4		0.19
MutPred		0.15		Loss of phosphorylation at T2176 (P = 0.0197)
MVP		0.39
MPC		0.10
ClinPred		0.31	T
GERP RS		2.6
Varity_R		0.064
gMVP		0.020
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs753301336; hg19: chr21-40568468;