X-80676917-C-T

Position:

chrX-80676917-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

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. 13/20 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:6

Conservation

PhyloP100: 0.954

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BRWD3. . Gene score misZ 4.269 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked syndromic intellectual disability, West syndrome, intellectual disability, X-linked 93, childhood epilepsy with centrotemporal spikes.

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 id is 210542.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chrX-80676917-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000307 (34/110779) while in subpopulation NFE AF= 0.000605 (32/52853). AF 95% confidence interval is 0.00044. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRWD3	NM_153252.5 linkuse as main transcript	c.5101G>A	p.Gly1701Arg	missense_variant	41/41	ENST00000373275.5	NP_694984.5	Q6RI45-1
BRWD3	XM_005262113.4 linkuse as main transcript	c.4951G>A	p.Gly1651Arg	missense_variant	40/40		XP_005262170.1
BRWD3	XM_017029384.2 linkuse as main transcript	c.3889G>A	p.Gly1297Arg	missense_variant	30/30		XP_016884873.1	Q6RI45-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRWD3	ENST00000373275.5 linkuse as main transcript	c.5101G>A	p.Gly1701Arg	missense_variant	41/41	1	NM_153252.5	ENSP00000362372.4		Q6RI45-1

Frequencies

GnomAD3 genomes

AF:

0.000307

AC:

AN:

110728

Hom.:

Cov.:

AF XY:

0.000273

AC XY:

AN XY:

32972

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

GnomAD3 exomes

AF:

0.000380

AC:

AN:

181491

Hom.:

AF XY:

0.000404

AC XY:

AN XY:

66863

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000380

Gnomad4 AMR exome

AF:

0.000228

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000124

Gnomad4 NFE exome

AF:

0.000942

Gnomad4 OTH exome

AF:

0.000523

GnomAD4 genome

AF:

0.000307

AC:

AN:

110779

Hom.:

Cov.:

AF XY:

0.000272

AC XY:

AN XY:

33033

show subpopulations

Gnomad4 AFR

AF:

0.0000328

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000169

Gnomad4 NFE

AF:

0.000605

Gnomad4 OTH

AF:

0.00

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:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2014

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

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 29, 2015

- -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Intellectual disability, X-linked 93

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

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

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

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

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

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