rs1557084239

Variant names:

• chrX-49076457-C-CA
• rs1557084239
• NM_001029896.2:c.408dupT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001029896.2(WDR45):​c.408dupT​(p.Glu137fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: WDR45 NM_001029896.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.28
• Publications: 0 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: Pathogenic. The variant received 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-49076457-C-CA is Pathogenic according to our data. Variant chrX-49076457-C-CA is described in ClinVar as Pathogenic. ClinVar VariationId is 540345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR45	NM_001029896.2	c.408dupT	p.Glu137fs	frameshift_variant	Exon 6 of 11	ENST00000376372.9	NP_001025067.1
WDR45	NM_007075.4	c.411dupT	p.Glu138fs	frameshift_variant	Exon 7 of 12		NP_009006.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR45	ENST00000376372.9	c.408dupT	p.Glu137fs	frameshift_variant	Exon 6 of 11	1	NM_001029896.2	ENSP00000365551.3
ENSG00000288053	ENST00000376358.4	c.131-513dupT		intron_variant	Intron 3 of 7	2		ENSP00000365536.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

May 19, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.411dupT pathogenic mutation (also known as p.E138*), located in coding exon 5 of the WDR45 gene, results from a duplication of T at nucleotide position 411. This changes the amino acid from a glutamate to a stop codon within coding exon 5. Since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Neurodegeneration with brain iron accumulation 5 Pathogenic:1

Apr 02, 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.Glu138*) 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 beta-propeller protein-associated neurodegeneration (PMID: 32307390). ClinVar contains an entry for this variant (Variation ID: 540345). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1557084239; hg19: chrX-48934116;