rs142085721

chrX-80744248-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_153252.5(BRWD3):c.597A>C(p.Ser199=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.131

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 -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 GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRWD3	NM_153252.5	c.597A>C	p.Ser199=	synonymous_variant	8/41	ENST00000373275.5
BRWD3	XM_005262113.4	c.597A>C	p.Ser199=	synonymous_variant	8/40
BRWD3	XM_047441957.1	c.597A>C	p.Ser199=	synonymous_variant	8/38
BRWD3	XM_017029385.3	c.597A>C	p.Ser199=	synonymous_variant	8/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRWD3	ENST00000373275.5	c.597A>C	p.Ser199=	synonymous_variant	8/41	1	NM_153252.5	P1
BRWD3	ENST00000478415.1	n.809A>C		non_coding_transcript_exon_variant	8/8	5

Frequencies

GnomAD3 genomes AF: 0.00504 AC: 564 AN: 111934 Hom.: 4 Cov.: 23 AF XY: 0.00466 AC XY: 159 AN XY: 34100

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.: 4 AF XY: 0.00460 AC XY: 312 AN XY: 67775

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.: 33 Cov.: 28 AF XY: 0.00810 AC XY: 2845 AN XY: 351119

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.: 4 Cov.: 23 AF XY: 0.00465 AC XY: 159 AN XY: 34159

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.: 35

Bravo AF: 0.00443

EpiCase AF: 0.00911

EpiControl AF: 0.00789

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2019	- -

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

Other links and lift over

dbSNP: rs142085721; hg19: chrX-79999747; COSMIC: COSV100956553;