rs797046101

Variant names:

• chrX-49076469-G-A
• rs797046101
• NM_001029896.2:c.397C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-49076469-G-A
• chrX-49076469-G-C

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.Arg133*) 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:11
• 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]

ENSG00000288053 (HGNC:):

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 rank	MANE	Protein	UniProt
WDR45	NM_001029896.2	c.397C>T	p.Arg133*	stop_gained	Exon 6 of 11	ENST00000376372.9	NP_001025067.1
WDR45	NM_007075.4	c.400C>T	p.Arg134*	stop_gained	Exon 7 of 12		NP_009006.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR45	ENST00000376372.9	c.397C>T	p.Arg133*	stop_gained	Exon 6 of 11	1	NM_001029896.2	ENSP00000365551.3
ENSG00000288053	ENST00000376358.4	c.131-524C>T		intron_variant	Intron 3 of 7	2		ENSP00000365536.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodegeneration with brain iron accumulation 5 Pathogenic:7

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 212592). For these reasons, this variant has been classified as Pathogenic. -

Mar 06, 2018

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS2, PS4, PM2 -

-

Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2022

Laboratory of Human Genetics, Universidade de São Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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. -

Feb 09, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:2

Apr 20, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Oct 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Aug 02, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.400C>T (p.R134*) alteration, located in exon 7 (coding exon 5) of the WDR45 gene, consists of a C to T substitution at nucleotide position 400. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 134. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined as heterozygous or has been determined to be the result of a de novo mutation in multiple individuals with seizures, absent speech, intellectual disability, specific MRI findings, cognitive dysfunction, and/or other clinical features consistent with beta-propeller protein-associated neurodegeneration (Haack, 2012; Nishioka, 2015; Chen, 2018). Based on the available evidence, this alteration is classified as pathogenic. -

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

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;