X-80670170-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_153252.5(BRWD3):c.*6439G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 110,281 control chromosomes in the GnomAD database, including 1 homozygotes. There are 38 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0013 (1 hom., 38 hem., cov: 22)
• Consequence: BRWD3 NM_153252.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.105

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-80670170-C-T is Benign according to our data. Variant chrX-80670170-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 368682.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00127 (140/110281) while in subpopulation NFE AF= 0.00153 (81/52770). AF 95% confidence interval is 0.00127. There are 1 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 38 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRWD3	NM_153252.5	c.*6439G>A		3_prime_UTR_variant	41/41	ENST00000373275.5
BRWD3	XM_005262113.4	c.*6439G>A		3_prime_UTR_variant	40/40
BRWD3	XM_017029384.2	c.*6439G>A		3_prime_UTR_variant	30/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRWD3	ENST00000373275.5	c.*6439G>A		3_prime_UTR_variant	41/41	1	NM_153252.5	P1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 140 AN: 110230 Hom.: 1 Cov.: 22 AF XY: 0.00117 AC XY: 38 AN XY: 32552

Gnomad AFR AF: 0.000330

Gnomad AMI AF: 0.00740

Gnomad AMR AF: 0.00107

Gnomad ASJ AF: 0.0114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00847

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.000680

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00127 AC: 140 AN: 110281 Hom.: 1 Cov.: 22 AF XY: 0.00117 AC XY: 38 AN XY: 32613

Gnomad4 AFR AF: 0.000329

Gnomad4 AMR AF: 0.00106

Gnomad4 ASJ AF: 0.0114

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.000671

Alfa AF: 0.00124 Hom.: 4

Bravo AF: 0.00127

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, X-linked 93 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

BRWD3: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.38
Dann	Benign	0.59

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs375704347; hg19: chrX-79925669;