rs1131691592

Variant names:

• chrX-49075882-C-T
• rs1131691592
• NM_001029896.2:c.500G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G167D) has been classified as Uncertain significance.

• 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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• neurodegeneration with brain iron accumulation 5

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288053 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-49075883-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3901154.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR45	ENST00000376372.9	c.500G>A	p.Gly167Glu	missense_variant	Exon 7 of 11	1	NM_001029896.2	ENSP00000365551.3
ENSG00000288053	ENST00000376358.4	c.194G>A	p.Gly65Glu	missense_variant	Exon 4 of 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

Aug 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 01, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		7.4
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
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.91
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1131691592; hg19: chrX-48933541;