rs142085721

Positions:

chrX-80744248-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_153252.5(BRWD3):c.597A>C(p.Ser199Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00819 in 1,197,146 control chromosomes in the GnomAD database, including 37 homozygotes. There are 3,004 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 4 hom., 159 hem., cov: 23)

Exomes 𝑓: 0.0085 ( 33 hom. 2845 hem. )

Consequence

BRWD3
NM_153252.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.131

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:

BRWD3 (HGNC:):

BRWD3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant X-80744248-T-G is Benign according to our data. Variant chrX-80744248-T-G is described in ClinVar as [Benign]. Clinvar id is 210543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-80744248-T-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.131 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00504 (564/111983) while in subpopulation NFE AF= 0.00927 (493/53180). AF 95% confidence interval is 0.00859. There are 4 homozygotes in gnomad4. There are 159 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRWD3	NM_153252.5 linkuse as main transcript	c.597A>C	p.Ser199Ser	synonymous_variant	8/41	ENST00000373275.5	NP_694984.5	Q6RI45-1
BRWD3	XM_005262113.4 linkuse as main transcript	c.597A>C	p.Ser199Ser	synonymous_variant	8/40		XP_005262170.1
BRWD3	XM_047441957.1 linkuse as main transcript	c.597A>C	p.Ser199Ser	synonymous_variant	8/38		XP_047297913.1
BRWD3	XM_017029385.3 linkuse as main transcript	c.597A>C	p.Ser199Ser	synonymous_variant	8/22		XP_016884874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRWD3	ENST00000373275.5 linkuse as main transcript	c.597A>C	p.Ser199Ser	synonymous_variant	8/41	1	NM_153252.5	ENSP00000362372.4		Q6RI45-1
BRWD3	ENST00000478415.1 linkuse as main transcript	n.809A>C		non_coding_transcript_exon_variant	8/8	5

Frequencies

GnomAD3 genomes

AF:

0.00504

AC:

564

AN:

111934

Hom.:

Cov.:

AF XY:

0.00466

AC XY:

159

AN XY:

34100

show subpopulations

Gnomad AFR

AF:

0.00117

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000287

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00476

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00927

Gnomad OTH

AF:

0.00199

GnomAD3 exomes

AF:

0.00490

AC:

897

AN:

183227

Hom.:

AF XY:

0.00460

AC XY:

312

AN XY:

67775

show subpopulations

Gnomad AFR exome

AF:

0.000990

Gnomad AMR exome

AF:

0.000475

Gnomad ASJ exome

AF:

0.000267

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00407

Gnomad NFE exome

AF:

0.00955

Gnomad OTH exome

AF:

0.00510

GnomAD4 exome

AF:

0.00851

AC:

9239

AN:

1085163

Hom.:

Cov.:

AF XY:

0.00810

AC XY:

2845

AN XY:

351119

show subpopulations

Gnomad4 AFR exome

AF:

0.000917

Gnomad4 AMR exome

AF:

0.000370

Gnomad4 ASJ exome

AF:

0.000518

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00415

Gnomad4 NFE exome

AF:

0.0106

Gnomad4 OTH exome

AF:

0.00515

GnomAD4 genome

AF:

0.00504

AC:

564

AN:

111983

Hom.:

Cov.:

AF XY:

0.00465

AC XY:

159

AN XY:

34159

show subpopulations

Gnomad4 AFR

AF:

0.00117

Gnomad4 AMR

AF:

0.000287

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00476

Gnomad4 NFE

AF:

0.00927

Gnomad4 OTH

AF:

0.00197

Alfa

AF:

0.00571

Hom.:

Bravo

AF:

0.00443

EpiCase

AF:

0.00911

EpiControl

AF:

0.00789

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 12, 2016

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Intellectual disability, X-linked 93

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

5.8

DANN

Benign

0.67

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