chrX-49076469-G-A

Position:

• chrX-49076469-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001029896.2(WDR45):​c.397C>T​(p.Arg133Ter) variant causes a stop gained change involving the alteration of a non-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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: WDR45 NM_001029896.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.25

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-49076469-G-A is Pathogenic according to our data. Variant chrX-49076469-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49076469-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR45	NM_001029896.2	c.397C>T	p.Arg133Ter	stop_gained	6/11	ENST00000376372.9
WDR45	NM_007075.4	c.400C>T	p.Arg134Ter	stop_gained	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR45	ENST00000376372.9	c.397C>T	p.Arg133Ter	stop_gained	6/11	1	NM_001029896.2	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodegeneration with brain iron accumulation 5 Pathogenic:7

Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Feb 09, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 02, 2021	PVS1, PS2, PS4, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 07, 2015	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Human Genetics, Universidade de São Paulo	Mar 16, 2022	This variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and in-silico evaluation of pathogenicity. This variant was disclosed in a girl presenting with intellectual disability and X-chromosome inactivation skewing. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 26, 2023	This premature translational stop signal has been observed in individual(s) with neurodegeneration with brain iron accumulation (NBIA), epileptic spasms and developmental delay, and West syndrome (PMID: 23176820, 25744623, 26609730, 27030146). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 212592). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg134*) in the WDR45 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WDR45 are known to be pathogenic (PMID: 23176820, 24368176, 24621584, 25744623, 26790960, 27030146, 27652284, 28554332). -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Mar 06, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23176820, 29981852, 25744623, 23687123, 26609730, 30369941, 25326635, 29445477, 27030146, 33084218, 33843443, 34077496) -

X-linked cerebral-cerebellar-coloboma syndrome syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2017

This variant was previously reported as pathogenic and was found once in our laboratory de novo in a 3-year-old female with infantile spasms, global developmental delay, and normal brain MRI. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.28	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;N
Vest4		0.88
ClinPred		0.99	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs797046101; hg19: chrX-48934128; COSMIC: COSV59876454; COSMIC: COSV59876454;