rs782302447

Positions:

• chrX-49076514-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001029896.2(WDR45):​c.352G>A​(p.Val118Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,098,082 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000014 (0 hom. 6 hem.)
• Consequence: WDR45 NM_001029896.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.71

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_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR45	NM_001029896.2	c.352G>A	p.Val118Met	missense_variant	6/11	ENST00000376372.9	NP_001025067.1
WDR45	NM_007075.4	c.355G>A	p.Val119Met	missense_variant	7/12		NP_009006.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR45	ENST00000376372.9	c.352G>A	p.Val118Met	missense_variant	6/11	1	NM_001029896.2	ENSP00000365551.3
ENSG00000288053	ENST00000376358.4	c.131-569G>A		intron_variant		2		ENSP00000365536.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000273 AC: 5 AN: 183333 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67781

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 15 AN: 1098082 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 6 AN XY: 363458

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000143

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodegeneration with brain iron accumulation 5 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 25, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt WDR45 protein function. ClinVar contains an entry for this variant (Variation ID: 431721). This missense change has been observed in individual(s) with atypical cerebral palsy (PMID: 30542205). This variant is present in population databases (rs782302447, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 119 of the WDR45 protein (p.Val119Met). -
Uncertain significance, criteria provided, single submitter	research	TIDEX, University of British Columbia	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;.;.;.;.;T;.;T;T;T;.;T;T;.;.;T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	.;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.2	M;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N;.;.;N;N;N;N;N;.;.;N;.;N;.;.;N;N;.
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D;.;.;D;D;D;D;D;.;.;D;.;D;.;.;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;.;.;.;.;.;D;.;.;.
Polyphen		0.99	D;D;.;D;D;D;P;D;.;.;.;.;.;.;.;.;.;.
Vest4		0.38
MutPred		0.68		Gain of MoRF binding (P = 0.0968);Gain of MoRF binding (P = 0.0968);Gain of MoRF binding (P = 0.0968);Gain of MoRF binding (P = 0.0968);.;.;Gain of MoRF binding (P = 0.0968);.;.;.;.;Gain of MoRF binding (P = 0.0968);.;.;Gain of MoRF binding (P = 0.0968);.;Gain of MoRF binding (P = 0.0968);.;
MVP		0.76
MPC		1.1
ClinPred		0.78	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs782302447; hg19: chrX-48934173;