21-39196921-T-C

Position:

chr21-39196921-T-C

Variant summary

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

The NM_033656.4(BRWD1):c.6148A>G(p.Thr2050Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000691 in 1,613,902 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0038 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 8 hom. )

Consequence

BRWD1
NM_033656.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.239

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=0.0026720762).

BP6

Variant 21-39196921-T-C is Benign according to our data. Variant chr21-39196921-T-C is described in ClinVar as [Benign]. Clinvar id is 3056259.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRWD1	NM_033656.4 linkuse as main transcript	c.6148A>G	p.Thr2050Ala	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.6148A>G	p.Thr2050Ala	missense_variant	41/41	1	NM_033656.4	A2	Q9NSI6-2
BRWD1	ENST00000333229.6 linkuse as main transcript	c.6148A>G	p.Thr2050Ala	missense_variant	41/42	1		P2	Q9NSI6-1
BRWD1	ENST00000380800.7 linkuse as main transcript	c.6148A>G	p.Thr2050Ala	missense_variant	41/42	1		A2	Q9NSI6-3
BRWD1	ENST00000446924.5 linkuse as main transcript	c.*2472A>G		3_prime_UTR_variant, NMD_transcript_variant	25/26	2

Frequencies

GnomAD3 genomes

AF:

0.00382

AC:

582

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00287

GnomAD3 exomes

AF:

0.000971

AC:

243

AN:

250352

Hom.:

AF XY:

0.000695

AC XY:

AN XY:

135302

show subpopulations

Gnomad AFR exome

AF:

0.0145

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000365

AC:

533

AN:

1461602

Hom.:

Cov.:

AF XY:

0.000316

AC XY:

230

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.0144

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.00382

AC:

582

AN:

152300

Hom.:

Cov.:

AF XY:

0.00407

AC XY:

303

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0137

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000462

Hom.:

Bravo

AF:

0.00435

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00132

AC:

160

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

BRWD1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2019

This variant is classified as 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

0.060

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

5.8

DANN

Benign

0.099

DEOGEN2

Benign

0.032

T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0079

LIST_S2

Benign

0.33

T;T;T

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

N;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.18

PROVEAN

Benign

0.14

N;N;N

REVEL

Benign

0.044

Sift

Benign

0.72

T;T;T

Sift4G

Benign

0.94

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.013

MVP

0.17

MPC

0.062

ClinPred

0.00095

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.032

gMVP

0.024

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