X-49074880-CAT-C

Variant names:

• chrX-49074880-CAT-C
• rs387907328
• NM_001029896.2:c.1004_1005delAT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001029896.2(WDR45):​c.1004_1005delAT​(p.Tyr335CysfsTer5) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: WDR45 NM_001029896.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.51

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0729 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-49074880-CAT-C is Pathogenic according to our data. Variant chrX-49074880-CAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 41911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49074880-CAT-C is described in Lovd as [Pathogenic]. Variant chrX-49074880-CAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR45	NM_001029896.2	c.1004_1005delAT	p.Tyr335CysfsTer5	frameshift_variant	Exon 11 of 11	ENST00000376372.9	NP_001025067.1
WDR45	NM_007075.4	c.1007_1008delAT	p.Tyr336CysfsTer5	frameshift_variant	Exon 12 of 12		NP_009006.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR45	ENST00000376372.9	c.1004_1005delAT	p.Tyr335CysfsTer5	frameshift_variant	Exon 11 of 11	1	NM_001029896.2	ENSP00000365551.3
ENSG00000288053	ENST00000376358.4	c.521+482_521+483delAT		intron_variant	Intron 6 of 7	2		ENSP00000365536.3

Frequencies

GnomAD3 genomes Cov.: 24

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

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodegeneration with brain iron accumulation 5 Pathogenic:6

Jun 26, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12826609, 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000012366 /PMID: 1565144) and different missense changes at the same codon (p.Arg273Cys, p.Arg273Gly, p.Arg273Leu, p.Arg273Pro, p.Arg273Ser / ClinVar ID: VCV000043594, VCV000231060, VCV000376655, VCV000376656, VCV000634682 /PMID: 10864200, 11180592, 8164043, 8425176, 8479749) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been previously reported as de novo in a similarly affected individual (PMID: 12672316). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10864200, 15390294, 1565144, 16401470, 7732013, 9242456). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1_Strong+PS4_Moderate+PM6_Strong -

Aug 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

See cases Pathogenic:1

Jun 24, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1, PS4, PM2, PM6 -

not provided Pathogenic:1

Jun 04, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation, as the last 26 amino acids are replaced with 4 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29171013, 29445477, 31069529, 23176820, 27681470) -

Computational scores

Source: dbNSFP v4.3

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: rs387907328; hg19: chrX-48932539;