X-49077702-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_001029896.2(WDR45):c.176G>A(p.Arg59His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,087,260 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

WDR45
NM_001029896.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.21

Publications

0 publications found

Variant links:

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

WDR45 links:

ENSG00000288053 (HGNC:):

ENSG00000288053 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001029896.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR45	NM_001029896.2 link	c.176G>A	p.Arg59His	missense_variant	Exon 4 of 11	ENST00000376372.9	NP_001025067.1	Q9Y484-1A0A024QYX1
WDR45	NM_007075.4 link	c.176G>A	p.Arg59His	missense_variant	Exon 5 of 12		NP_009006.2	Q9Y484-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR45	ENST00000376372.9 link	c.176G>A	p.Arg59His	missense_variant	Exon 4 of 11	1	NM_001029896.2	ENSP00000365551.3		Q9Y484-1
ENSG00000288053	ENST00000376358.4 link	c.130+135G>A		intron_variant	Intron 3 of 7	2		ENSP00000365536.3		A6NM71

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1087260

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

355280

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26145

American (AMR)

AF:

0.00

AC:

AN:

33868

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19134

East Asian (EAS)

AF:

0.00

AC:

AN:

29586

South Asian (SAS)

AF:

0.0000191

AC:

AN:

52315

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39724

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4121

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

836635

Other (OTH)

AF:

0.00

AC:

AN:

45732

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Oct 06, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.176G>A (p.R59H) alteration is located in exon 5 (coding exon 3) of the WDR45 gene. This alteration results from a G to A substitution at nucleotide position 176, causing the arginine (R) at amino acid position 59 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

T;T;T;.;T;.;.;T;.;T;.;T;T;.;T;T;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Pathogenic

3.2

M;M;.;.;.;M;M;.;M;.;.;.;.;.;.;.;.

PhyloP100

7.2

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.7

D;.;.;.;.;D;D;D;D;.;D;D;.;D;D;.;.

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

D;.;.;.;.;D;D;D;D;.;D;D;.;D;D;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;.;.;.;.;D;.;.;D

Polyphen

0.88

P;P;.;.;.;D;D;D;D;.;.;.;.;.;.;.;.

Vest4

0.52

MutPred

0.50

Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;.;

MVP

0.67

MPC

1.7

ClinPred

1.0

GERP RS

3.6

PromoterAI

0.013

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.54

Mutation Taster

=71/29

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over