X-49075882-C-T

Position:

• chrX-49075882-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001029896.2(WDR45):​c.500G>A​(p.Gly167Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: WDR45 NM_001029896.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.42

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]

ENSG00000288053 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant X-49075882-C-T is Pathogenic according to our data. Variant chrX-49075882-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49075882-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR45	NM_001029896.2	c.500G>A	p.Gly167Glu	missense_variant	7/11	ENST00000376372.9	NP_001025067.1
WDR45	NM_007075.4	c.503G>A	p.Gly168Glu	missense_variant	8/12		NP_009006.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR45	ENST00000376372.9	c.500G>A	p.Gly167Glu	missense_variant	7/11	1	NM_001029896.2	ENSP00000365551.3
ENSG00000288053	ENST00000376358.4	c.194G>A	p.Gly65Glu	missense_variant	4/8	2		ENSP00000365536.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodegeneration with brain iron accumulation 5 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 2017

The G168E variant in the WDR45 gene has not been published previously as a pathogenic variant nor as a benign variant, to our knowledge. It has been reported as a de novo variant with confirmed parentage in multiple patients with neurodevelopmental disorders who were previously tested at GeneDx. The G168E variant was not observed in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server). The G168E variant is a non-conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We consider G168E a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T;T;T;T;.;T;.;.;.;D;.;T;.;T;T;.;D;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;.;T;T;T;T;T;.;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.7	.;H;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.0	D;D;.;.;.;.;D;D;D;D;D;.;.;.;D;.;D;.;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;D;.;.;.;.;D;D;D;D;D;.;.;.;D;.;D;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D;D;.;.;.;.;.;.;D
Polyphen		1.0	D;D;D;.;.;.;D;D;D;D;D;.;.;.;.;.;.;.;.
Vest4		0.91
MutPred		0.51		.;Gain of solvent accessibility (P = 0.1045);Gain of solvent accessibility (P = 0.1045);.;Gain of solvent accessibility (P = 0.1045);.;.;.;.;Gain of solvent accessibility (P = 0.1045);.;.;.;.;.;.;.;.;Gain of solvent accessibility (P = 0.1045);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1131691592; hg19: chrX-48933541;