X-49074847-CCT-C

Variant names:

• chrX-49074847-CCT-C
• NM_001029896.2:c.1037_1038delAG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001029896.2(WDR45):​c.1037_1038delAG​(p.Glu346GlyfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. 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, single submitter P:1
• Conservation: PhyloP100: 7.25

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 Likely_pathogenic. Variant got 6 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 0.0425 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-49074847-CCT-C is Pathogenic according to our data. Variant chrX-49074847-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 1386002.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-49074847-CCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR45	NM_001029896.2	c.1037_1038delAG	p.Glu346GlyfsTer7	frameshift_variant	Exon 11 of 11	ENST00000376372.9	NP_001025067.1
WDR45	NM_007075.4	c.1040_1041delAG	p.Glu347GlyfsTer7	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.1037_1038delAG	p.Glu346GlyfsTer7	frameshift_variant	Exon 11 of 11	1	NM_001029896.2	ENSP00000365551.3
ENSG00000288053	ENST00000376358.4	c.521+515_521+516delAG		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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodegeneration with brain iron accumulation 5 Pathogenic:1

Jun 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects WDR45 function (PMID: 31332960). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This premature translational stop signal has been observed in individual(s) with clinical features of WDR45-related conditions (PMID: 31332960). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu347Glyfs*7) in the WDR45 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15 amino acid(s) of the WDR45 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-48932506;