rs1326742832

Positions:

chrX-49077742-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001029896.2(WDR45):c.136G>A(p.Glu46Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000751 in 1,198,687 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000064 ( 0 hom. 3 hem. )

Consequence

WDR45
NM_001029896.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.21

Variant links:

Genes affected

WDR45 (HGNC:28912): (WD repeat domain 45) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This gene has a pseudogene at chromosome 4q31.3. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity and full-length nature of some variants have not been determined. [provided by RefSeq, Jul 2008]

WDR45 links:

ENSG00000288053 (HGNC:):

ENSG00000288053 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.36060816).

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR45	NM_001029896.2 linkuse as main transcript	c.136G>A	p.Glu46Lys	missense_variant	4/11	ENST00000376372.9	NP_001025067.1	Q9Y484-1A0A024QYX1
WDR45	NM_007075.4 linkuse as main transcript	c.136G>A	p.Glu46Lys	missense_variant	5/12		NP_009006.2	Q9Y484-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR45	ENST00000376372.9 linkuse as main transcript	c.136G>A	p.Glu46Lys	missense_variant	4/11	1	NM_001029896.2	ENSP00000365551.3		Q9Y484-1
ENSG00000288053	ENST00000376358.4 linkuse as main transcript	c.130+95G>A		intron_variant		2		ENSP00000365536.3		A6NM71

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112123

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34279

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000644

AC:

AN:

1086564

Hom.:

Cov.:

AF XY:

0.00000846

AC XY:

AN XY:

354564

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000338

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000718

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112123

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34279

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neurodegeneration with brain iron accumulation 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 03, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 46 of the WDR45 protein (p.Glu46Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with WDR45-related conditions. ClinVar contains an entry for this variant (Variation ID: 540349). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WDR45 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.071

T;T;T;.;T;.;.;T;.;T;.;T;T;.;T;T;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.36

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.92

L;L;.;.;.;L;L;.;L;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.5

N;.;.;.;.;N;N;N;N;.;N;N;N;N;N;.;.

REVEL

Benign

0.18

Sift

Benign

0.83

T;.;.;.;.;T;T;T;T;.;T;T;T;T;T;.;.

Sift4G

Benign

0.82

T;T;T;T;T;T;T;T;T;.;.;.;.;T;.;.;T

Polyphen

0.0

B;B;.;.;.;B;B;B;B;.;.;.;.;.;.;.;.

Vest4

0.39

MutPred

0.42

Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);.;Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);.;.;

MVP

0.51

MPC

0.69

ClinPred

0.90

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.33

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over