X-49074887-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001029896.2(WDR45):c.999C>G(p.His333Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,122 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: WDR45 NM_001029896.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.05

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR45	NM_001029896.2	c.999C>G	p.His333Gln	missense_variant	11/11	ENST00000376372.9
WDR45	NM_007075.4	c.1002C>G	p.His334Gln	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR45	ENST00000376372.9	c.999C>G	p.His333Gln	missense_variant	11/11	1	NM_001029896.2	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097122 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362498

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

WDR45-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2023

The WDR45 c.1002C>G variant is predicted to result in the amino acid substitution p.His334Gln. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;T;.;T;.;.;.;.;T
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.7	M;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.0	D;.;.;.;.;D;D;D;D;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.0040	D;.;.;.;.;D;D;D;D;.
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D;D;D;D
Polyphen		0.43	B;B;.;.;.;D;D;D;D;.
Vest4		0.66
MutPred		0.61		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;.;.;.;.;.;.;.;
MVP		0.59
MPC		1.1
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.86
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-48932546; COSMIC: COSV59876576; COSMIC: COSV59876576;