X-80670819-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.*5790G>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 0.000967 in 111,736 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 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 0.00097 (0 hom., 35 hem., cov: 23)
  • Failed GnomAD Quality Control
• Consequence: BRWD3 NM_153252.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.791

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=-0.95).
• BP6: Variant X-80670819-C-T is Benign according to our data. Variant chrX-80670819-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 368688.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000967 (108/111736) while in subpopulation SAS AF= 0.00516 (14/2711). AF 95% confidence interval is 0.00312. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 35 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRWD3	NM_153252.5	c.*5790G>A		3_prime_UTR_variant	41/41	ENST00000373275.5
BRWD3	XM_005262113.4	c.*5790G>A		3_prime_UTR_variant	40/40
BRWD3	XM_017029384.2	c.*5790G>A		3_prime_UTR_variant	30/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRWD3	ENST00000373275.5	c.*5790G>A		3_prime_UTR_variant	41/41	1	NM_153252.5	P1

Frequencies

GnomAD3 genomes AF: 0.000967 AC: 108 AN: 111680 Hom.: 0 Cov.: 23 AF XY: 0.00103 AC XY: 35 AN XY: 33846

Gnomad AFR AF: 0.000228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000478

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.00515

Gnomad FIN AF: 0.000503

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00145

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.000967 AC: 108 AN: 111736 Hom.: 0 Cov.: 23 AF XY: 0.00103 AC XY: 35 AN XY: 33912

Gnomad4 AFR AF: 0.000227

Gnomad4 AMR AF: 0.000477

Gnomad4 ASJ AF: 0.000377

Gnomad4 EAS AF: 0.000283

Gnomad4 SAS AF: 0.00516

Gnomad4 FIN AF: 0.000503

Gnomad4 NFE AF: 0.00145

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00114 Hom.: 4

Bravo AF: 0.000706

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 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, 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

Nov 01, 2022

BRWD3: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.55
Dann	Benign	0.33

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs759779733; hg19: chrX-79926318;