rs112829587

Positions:

• chrX-80744076-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153252.5(BRWD3):​c.769G>A​(p.Val257Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000304 in 1,209,519 control chromosomes in the GnomAD database, including 2 homozygotes. There are 92 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., 46 hem., cov: 23)
  • Exomes 𝑓: 0.00017 (1 hom. 46 hem.)
• Consequence: BRWD3 NM_153252.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.560

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]

ACMG classification

Verdict is Benign. Variant got -19 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=0.007643521).
• BP6: Variant X-80744076-C-T is Benign according to our data. Variant chrX-80744076-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 198921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00162 (181/111684) while in subpopulation AFR AF= 0.00582 (179/30754). AF 95% confidence interval is 0.00512. There are 1 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 46 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRWD3	NM_153252.5	c.769G>A	p.Val257Ile	missense_variant	8/41	ENST00000373275.5
BRWD3	XM_005262113.4	c.769G>A	p.Val257Ile	missense_variant	8/40
BRWD3	XM_047441957.1	c.769G>A	p.Val257Ile	missense_variant	8/38
BRWD3	XM_017029385.3	c.769G>A	p.Val257Ile	missense_variant	8/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRWD3	ENST00000373275.5	c.769G>A	p.Val257Ile	missense_variant	8/41	1	NM_153252.5	P1
BRWD3	ENST00000478415.1	n.981G>A		non_coding_transcript_exon_variant	8/8	5

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 180 AN: 111629 Hom.: 1 Cov.: 23 AF XY: 0.00133 AC XY: 45 AN XY: 33813

Gnomad AFR AF: 0.00580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000957

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000404 AC: 74 AN: 183201 Hom.: 1 AF XY: 0.000207 AC XY: 14 AN XY: 67733

Gnomad AFR exome AF: 0.00555

Gnomad AMR exome AF: 0.00

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000170 AC: 187 AN: 1097835 Hom.: 1 Cov.: 30 AF XY: 0.000127 AC XY: 46 AN XY: 363253

Gnomad4 AFR exome AF: 0.00538

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000440

Gnomad4 OTH exome AF: 0.000130

GnomAD4 genome AF: 0.00162 AC: 181 AN: 111684 Hom.: 1 Cov.: 23 AF XY: 0.00136 AC XY: 46 AN XY: 33878

Gnomad4 AFR AF: 0.00582

Gnomad4 AMR AF: 0.0000956

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000153 Hom.: 7

Bravo AF: 0.00160

ESP6500AA AF: 0.00548 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 23, 2018	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2017

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 12, 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
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.58	N
MutationTaster	Benign	0.60	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.096
Sift	Benign	0.55	T
Sift4G	Benign	0.16	T
Polyphen		0.65	P
Vest4		0.21
MVP		0.63
MPC		0.77
ClinPred		0.026	T
GERP RS		3.5
Varity_R		0.071
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs112829587; hg19: chrX-79999575;