rs387907329

chrX-49075573-G-AchrX-49075573-G-T

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.697C>T(p.Arg233Ter) 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: WDR45 NM_001029896.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 1.29

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-49075573-G-A is Pathogenic according to our data. Variant chrX-49075573-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 41912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49075573-G-A is described in Lovd as [Pathogenic]. Variant chrX-49075573-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR45	NM_001029896.2	c.697C>T	p.Arg233Ter	stop_gained	8/11	ENST00000376372.9
WDR45	NM_007075.4	c.700C>T	p.Arg234Ter	stop_gained	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR45	ENST00000376372.9	c.697C>T	p.Arg233Ter	stop_gained	8/11	1	NM_001029896.2	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodegeneration with brain iron accumulation 5 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 16, 2023	This premature translational stop signal has been observed in individual(s) with neurodegeneration with brain iron accumulation (PMID: 23176820, 23687123, 28932395, 29171013, 29981852). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 41912). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg234*) 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, no assertion criteria provided	literature only	OMIM	Dec 07, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 17, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	research	TIDEX, University of British Columbia	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 17, 2022	PVS1 PS2 PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2022	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: 27159028, 23687123, 23176820, 26795593, 28932395, 29171013, 26725113, 29286531, 30842224, 31618753, 33504798, 30542205, 34490615, 32342562, 29981852, 31785789) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2019	- -

Seizure;C0344482:Hypoplasia of the corpus callosum;C0454644:Delayed speech and language development;C0557874:Global developmental delay;C1837658:Delayed gross motor development;C1854882:Absent speech Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 01, 2014

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2014

The c.700C>T (p.R234*) alteration, located in exon 9 (coding exon 7) of the WDR45 gene, consists of a C to T substitution at nucleotide position 700. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 234. Premature stop codons are typically deleterious in nature (Richards, 2015). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the WDR45 c.700C>T (p.R234*) alteration was not observed among 6,453 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The amino acid change has been observed in affected individuals: _x000D_ The c.700C>T (p.R234*) alteration has been reported in a 39 year-old female patient with beta-propeller protein-associated neurodegeneration (BPAN), an X-linked dominant form of neurodegeneration with brain iron accumulation (Haack, 2012; Hayflick, 2013). This patient's phenotype included developmental delay and intellectual disability, progressive psychomotor slowing in adolescence, dystonia and Parkinsonism with a positive response to L-DOPA, limited expressive language, stroke, and epilepsy characterized by absence, atonic, and febrile seizures. Brain MRI in this patient revealed iron accumulation in the substantia nigra and globus pallidus and T1 hyperintense "halo" in the midbrain. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	35
Dann	Uncertain	1.0
FATHMM_MKL	Benign	0.69	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;D
Vest4		0.96
ClinPred		0.96	D
GERP RS		0.40

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: rs387907329; hg19: chrX-48933232; COSMIC: COSV59875527; COSMIC: COSV59875527;