rs864309661

Variant names:

• chrX-49077714-TCCA-T
• rs864309661
• NM_001029896.2:c.161_163delTGG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_001029896.2(WDR45):​c.161_163delTGG​(p.Val54del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: WDR45 NM_001029896.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.81
• Publications: 4 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_001029896.2
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001029896.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-49077714-TCCA-T is Pathogenic according to our data. Variant chrX-49077714-TCCA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218903.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR45	NM_001029896.2	c.161_163delTGG	p.Val54del	disruptive_inframe_deletion	Exon 4 of 11	ENST00000376372.9	NP_001025067.1
WDR45	NM_007075.4	c.161_163delTGG	p.Val54del	disruptive_inframe_deletion	Exon 5 of 12		NP_009006.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR45	ENST00000376372.9	c.161_163delTGG	p.Val54del	disruptive_inframe_deletion	Exon 4 of 11	1	NM_001029896.2	ENSP00000365551.3
ENSG00000288053	ENST00000376358.4	c.130+120_130+122delTGG		intron_variant	Intron 3 of 7	2		ENSP00000365536.3

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurodegeneration with brain iron accumulation 5 Pathogenic:1

May 20, 2015

Molecular Genetics Pathology Laboratory, University Of Arkansas for Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.161_163delTGG change is a previously unreported in-frame deletion that results in a deletion of a valine amino acid at codon 54 (p.Val54del). This residue is conserved across mammals, and the variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project and was absent in the Exome Aggregation Consortium (ExAC) database (http://exac.broadinstitute.org/). One other patient with BPAN has been previously reported to have an in-frame deletion in the WDR45 gene (c.752_754del, p.Ser251del). -

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

Sep 01, 2017

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was found once in our laboratory de novo in a 2-year-old male with global delays, dystonia, ataxia, structural brain abnormalities, seizures, sialorrhea, retractible testes. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=67/33	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs864309661; hg19: chrX-48935373;