21-39196602-T-C

Position:

chr21-39196602-T-C

Variant summary

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

The NM_033656.4(BRWD1):c.6467A>G(p.Lys2156Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,613,474 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 7 hom. )

Consequence

BRWD1
NM_033656.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.0640

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=0.0052030087).

BP6

Variant 21-39196602-T-C is Benign according to our data. Variant chr21-39196602-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3038361.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-39196602-T-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRWD1	NM_033656.4 linkuse as main transcript	c.6467A>G	p.Lys2156Arg	missense_variant	41/41	ENST00000342449.8	NP_387505.1	Q9NSI6-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRWD1	ENST00000342449.8 linkuse as main transcript	c.6467A>G	p.Lys2156Arg	missense_variant	41/41	1	NM_033656.4	ENSP00000344333.3		Q9NSI6-2

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

296

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00210

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00332

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00164

AC:

410

AN:

250542

Hom.:

AF XY:

0.00171

AC XY:

232

AN XY:

135464

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.000598

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00277

Gnomad OTH exome

AF:

0.00230

GnomAD4 exome

AF:

0.00245

AC:

3582

AN:

1461206

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

1670

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.000419

Gnomad4 AMR exome

AF:

0.00217

Gnomad4 ASJ exome

AF:

0.000958

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.00295

Gnomad4 OTH exome

AF:

0.00252

GnomAD4 genome

AF:

0.00194

AC:

296

AN:

152268

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

121

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000601

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00332

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00284

Hom.:

Bravo

AF:

0.00192

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00161

AC:

195

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00338

EpiControl

AF:

0.00202

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 30, 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

0.067

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

5.3

DANN

Benign

0.96

DEOGEN2

Benign

0.055

T;.;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.63

T;T;T

M_CAP

Benign

0.0042

MetaRNN

Benign

0.0052

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L;L

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.52

N;N;N

REVEL

Benign

0.040

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.63

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.044

MVP

0.48

MPC

0.057

ClinPred

0.0036

GERP RS

0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.042

gMVP

0.022

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