rs1326742832

chrX-49077742-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The NM_001029896.2(WDR45):c.136G>A(p.Glu46Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000751 in 1,198,687 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: WDR45 NM_001029896.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.21

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a repeat WD 2 (size 44) in uniprot entity WIPI4_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_001029896.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.36060816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR45	NM_001029896.2	c.136G>A	p.Glu46Lys	missense_variant	4/11	ENST00000376372.9
WDR45	NM_007075.4	c.136G>A	p.Glu46Lys	missense_variant	5/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR45	ENST00000376372.9	c.136G>A	p.Glu46Lys	missense_variant	4/11	1	NM_001029896.2	P4

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112123 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34279

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000644 AC: 7 AN: 1086564 Hom.: 0 Cov.: 30 AF XY: 0.00000846 AC XY: 3 AN XY: 354564

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000338

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000718

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112123 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34279

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodegeneration with brain iron accumulation 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 03, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 46 of the WDR45 protein (p.Glu46Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with WDR45-related conditions. ClinVar contains an entry for this variant (Variation ID: 540349). 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 not expected to disrupt WDR45 protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.071	T;T;T;.;T;.;.;T;.;T;.;T;T;.;T;T;.
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.92	L;L;.;.;.;L;L;.;L;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.5	N;.;.;.;.;N;N;N;N;.;N;N;N;N;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.83	T;.;.;.;.;T;T;T;T;.;T;T;T;T;T;.;.
Sift4G	Benign	0.82	T;T;T;T;T;T;T;T;T;.;.;.;.;T;.;.;T
Polyphen		0.0	B;B;.;.;.;B;B;B;B;.;.;.;.;.;.;.;.
Vest4		0.39
MutPred		0.42		Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);.;Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);Gain of ubiquitination at E46 (P = 0.0128);.;.;
MVP		0.51
MPC		0.69
ClinPred		0.90	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.33
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1326742832; hg19: chrX-48935401;