chr21-39197176-G-A

Position:

chr21-39197176-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_033656.4(BRWD1):c.5893C>T(p.Leu1965Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,614,114 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 18 hom. )

Consequence

BRWD1
NM_033656.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.416

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BRWD1. . Gene score misZ 2.8458 (greater than the threshold 3.09). Trascript score misZ 3.3525 (greater than threshold 3.09). GenCC has associacion of gene with ciliary dyskinesia, primary, 51, agammaglobulinemia, primary ciliary dyskinesia.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040858984).

BP6

Variant 21-39197176-G-A is Benign according to our data. Variant chr21-39197176-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3039911.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRWD1	NM_033656.4 linkuse as main transcript	c.5893C>T	p.Leu1965Phe	missense_variant	41/41	ENST00000342449.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRWD1	ENST00000342449.8 linkuse as main transcript	c.5893C>T	p.Leu1965Phe	missense_variant	41/41	1	NM_033656.4	A2	Q9NSI6-2
BRWD1	ENST00000333229.6 linkuse as main transcript	c.5893C>T	p.Leu1965Phe	missense_variant	41/42	1		P2	Q9NSI6-1
BRWD1	ENST00000380800.7 linkuse as main transcript	c.5893C>T	p.Leu1965Phe	missense_variant	41/42	1		A2	Q9NSI6-3
BRWD1	ENST00000446924.5 linkuse as main transcript	c.*2217C>T		3_prime_UTR_variant, NMD_transcript_variant	25/26	2

Frequencies

GnomAD3 genomes

AF:

0.00212

AC:

323

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00313

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00200

AC:

502

AN:

250874

Hom.:

AF XY:

0.00181

AC XY:

245

AN XY:

135584

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.00636

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00261

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00307

AC:

4481

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00297

AC XY:

2162

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00291

Gnomad4 ASJ exome

AF:

0.00651

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000301

Gnomad4 FIN exome

AF:

0.000711

Gnomad4 NFE exome

AF:

0.00351

Gnomad4 OTH exome

AF:

0.00326

GnomAD4 genome

AF:

0.00211

AC:

322

AN:

152306

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

157

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000625

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.00312

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00303

Hom.:

Bravo

AF:

0.00245

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00169

AC:

205

EpiCase

AF:

0.00294

EpiControl

AF:

0.00249

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

BRWD1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.88

DANN

Benign

0.72

DEOGEN2

Benign

0.068

T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.65

T;T;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.0041

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;M;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.72

N;N;N

REVEL

Benign

0.080

Sift

Benign

0.032

D;D;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.53

P;P;.

Vest4

0.029

MVP

0.34

MPC

0.12

ClinPred

0.010

GERP RS

0.85

Varity_R

0.11

gMVP

0.027

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over