X-49074841-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001029896.2(WDR45):c.1045G>A(p.Asp349Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000891 in 112,181 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 25)
• Consequence: WDR45 NM_001029896.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.15

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR45	NM_001029896.2	c.1045G>A	p.Asp349Asn	missense_variant	11/11	ENST00000376372.9
WDR45	NM_007075.4	c.1048G>A	p.Asp350Asn	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR45	ENST00000376372.9	c.1045G>A	p.Asp349Asn	missense_variant	11/11	1	NM_001029896.2	P4

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112181 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34367

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183494 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67928

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112181 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34367

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: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodegeneration with brain iron accumulation 5 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 25, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0110 - This gene is known to be associated with X-linked dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine (exon 12). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (0 heterozygotes, 1 hemizygote, 0 homozygotes). (P) 0309 - An alternative amino acid change to a histidine at the same position has been observed in gnomAD (0 heterozygotes, 1 hemizygote, 0 homozygotes). (N) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 350 of the WDR45 protein (p.Asp350Asn). This variant is present in population databases (rs781979357, gnomAD 0.001%), including at least one homozygous and/or hemizygous individual. 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: 1776135). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WDR45 protein function. 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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2018

The p.D350N variant (also known as c.1048G>A), located in coding exon 10 of the WDR45 gene, results from a G to A substitution at nucleotide position 1048. The aspartic acid at codon 350 is replaced by asparagine, an amino acid with highly similar properties. This variant did not co-segregate with disease in one individual tested in our laboratory. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;T;.;T;.;.;.;.;T
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.7	L;L;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.0	D;.;.;.;.;D;D;D;D;.
REVEL	Uncertain	0.49
Sift	Benign	0.17	T;.;.;.;.;T;T;T;T;.
Sift4G	Benign	0.40	T;T;T;T;T;T;T;T;T;T
Polyphen		0.98	D;D;.;.;.;D;D;D;D;.
Vest4		0.49
MutPred		0.59		Gain of catalytic residue at D349 (P = 0.1833);Gain of catalytic residue at D349 (P = 0.1833);.;.;.;.;.;.;.;.;
MVP		0.72
MPC		1.6
ClinPred		0.88	D
GERP RS		5.0
Varity_R		0.51
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs781979357; hg19: chrX-48932500; COSMIC: COSV59875974; COSMIC: COSV59875974;