rs187384754

Positions:

• chrX-80745587-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The ENST00000373275.5(BRWD3):​c.573C>T​(p.Ser191=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000986 in 1,206,455 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 42 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.000093 (0 hom. 37 hem.)
• Consequence: BRWD3 ENST00000373275.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.448

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant X-80745587-G-A is Benign according to our data. Variant chrX-80745587-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 434542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-80745587-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.448 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000154 (17/110574) while in subpopulation NFE AF= 0.000208 (11/52918). AF 95% confidence interval is 0.000116. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRWD3	NM_153252.5	c.573C>T	p.Ser191=	synonymous_variant	7/41	ENST00000373275.5	NP_694984.5
BRWD3	XM_005262113.4	c.573C>T	p.Ser191=	synonymous_variant	7/40		XP_005262170.1
BRWD3	XM_047441957.1	c.573C>T	p.Ser191=	synonymous_variant	7/38		XP_047297913.1
BRWD3	XM_017029385.3	c.573C>T	p.Ser191=	synonymous_variant	7/22		XP_016884874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRWD3	ENST00000373275.5	c.573C>T	p.Ser191=	synonymous_variant	7/41	1	NM_153252.5	ENSP00000362372	P1
BRWD3	ENST00000478415.1	n.785C>T		non_coding_transcript_exon_variant	7/8	5

Frequencies

GnomAD3 genomes AF: 0.000163 AC: 18 AN: 110522 Hom.: 0 Cov.: 23 AF XY: 0.000152 AC XY: 5 AN XY: 32846

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000973

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000173

Gnomad MID AF: 0.00844

Gnomad NFE AF: 0.000208

Gnomad OTH AF: 0.00201

GnomAD3 exomes AF: 0.000173 AC: 31 AN: 179689 Hom.: 0 AF XY: 0.000201 AC XY: 13 AN XY: 64659

Gnomad AFR exome AF: 0.0000772

Gnomad AMR exome AF: 0.0000738

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000313

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.0000931 AC: 102 AN: 1095881 Hom.: 0 Cov.: 30 AF XY: 0.000102 AC XY: 37 AN XY: 361651

Gnomad4 AFR exome AF: 0.0000759

Gnomad4 AMR exome AF: 0.0000856

Gnomad4 ASJ exome AF: 0.0000517

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.000154 AC: 17 AN: 110574 Hom.: 0 Cov.: 23 AF XY: 0.000152 AC XY: 5 AN XY: 32908

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000972

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000173

Gnomad4 NFE AF: 0.000208

Gnomad4 OTH AF: 0.00198

Alfa AF: 0.000260 Hom.: 3

Bravo AF: 0.000162

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	BRWD3: BP4, BP7 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 03, 2017

- -

BRWD3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2019

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.2
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs187384754; hg19: chrX-80001086; COSMIC: COSV100955752;