rs200751676

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_153252.5(BRWD3):c.5101G>A(p.Gly1701Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000715 in 1,203,059 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 280 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., 9 hem., cov: 22)

Exomes 𝑓: 0.00076 ( 0 hom. 271 hem. )

Consequence

BRWD3
NM_153252.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.954

Publications

0 publications found

Variant links:

Genes affected

BRWD3 (HGNC:17342): (bromodomain and WD repeat domain containing 3) The protein encoded by this gene contains a bromodomain and several WD repeats. It is thought to have a chromatin-modifying function, and may thus play a role in transcription. Mutations in this gene are associated with a spectrum of cognitive disabilities and X-linked macrocephaly. This gene is also associated with translocations in patients with B-cell chronic lymphocytic leukemia. [provided by RefSeq, Jul 2017]

BRWD3 Gene-Disease associations (from GenCC):

intellectual disability, X-linked 93
Inheritance: XL, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
X-linked syndromic intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
infantile spasms
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
self-limited epilepsy with centrotemporal spikes
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRWD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03294748).

BP6

Variant X-80676917-C-T is Benign according to our data. Variant chrX-80676917-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210542.

BS2

High AC in GnomAd4 at 34 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRWD3	NM_153252.5 link	c.5101G>A	p.Gly1701Arg	missense_variant	Exon 41 of 41	ENST00000373275.5	NP_694984.5	Q6RI45-1
BRWD3	NM_001441339.1 link	c.4951G>A	p.Gly1651Arg	missense_variant	Exon 40 of 40		NP_001428268.1
BRWD3	XM_017029384.2 link	c.3889G>A	p.Gly1297Arg	missense_variant	Exon 30 of 30		XP_016884873.1	Q6RI45-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRWD3	ENST00000373275.5 link	c.5101G>A	p.Gly1701Arg	missense_variant	Exon 41 of 41	1	NM_153252.5	ENSP00000362372.4		Q6RI45-1

Frequencies

GnomAD3 genomes

AF:

0.000307

AC:

AN:

110728

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000329

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:

0.000169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000605

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000380

AC:

AN:

181491

AF XY:

0.000404

show subpopulations

Gnomad AFR exome

AF:

0.0000764

Gnomad AMR exome

AF:

0.000331

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000632

Gnomad NFE exome

AF:

0.000693

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.000756

AC:

826

AN:

1092280

Hom.:

Cov.:

AF XY:

0.000757

AC XY:

271

AN XY:

358118

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26286

American (AMR)

AF:

0.000228

AC:

AN:

35112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19348

East Asian (EAS)

AF:

0.00

AC:

AN:

30124

South Asian (SAS)

AF:

0.00

AC:

AN:

53996

European-Finnish (FIN)

AF:

0.000124

AC:

AN:

40457

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4117

European-Non Finnish (NFE)

AF:

0.000942

AC:

788

AN:

836950

Other (OTH)

AF:

0.000523

AC:

AN:

45890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

116

154

193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000307

AC:

AN:

110779

Hom.:

Cov.:

AF XY:

0.000272

AC XY:

AN XY:

33033

show subpopulations

African (AFR)

AF:

0.0000328

AC:

AN:

30450

American (AMR)

AF:

0.00

AC:

AN:

10402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2636

East Asian (EAS)

AF:

0.00

AC:

AN:

3512

South Asian (SAS)

AF:

0.00

AC:

AN:

2583

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

5933

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.000605

AC:

AN:

52853

Other (OTH)

AF:

0.00

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000391

Hom.:

Bravo

AF:

0.000325

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Aug 18, 2014

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G1701R variant (also known as c.5101G>A), located in coding exon 41 of the BRWD3 gene, results from a G to A substitution at nucleotide position 5101. The glycine at codon 1701 is replaced by arginine, an amino acid with dissimilar properties. This variant was previously reported in the SNPDatabase as rs200751676. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele was absent out of 2443 total male alleles studied. This amino acid position is not conserved on species alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not specified

Benign:1

Jan 29, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Conotruncal heart malformations

Benign:1

Jun 21, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, X-linked 93

Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Intellectual disability

Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.097

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.82

M_CAP

Benign

0.033

MetaRNN

Benign

0.033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.95

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.71

REVEL

Benign

0.081

Sift

Uncertain

0.0030

Sift4G

Benign

0.58

Polyphen

0.0010

Vest4

0.15

MutPred

0.33

Gain of methylation at G1701 (P = 3e-04);

MVP

0.47

MPC

0.46

ClinPred

0.043

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.10

gMVP

0.52

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over