rs374078317

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 2P and 18B. PM1BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001029896.2(WDR45):c.566A>G(p.Asn189Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,208,659 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 70 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N189N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.00017 ( 0 hom. 67 hem. )

Consequence

WDR45
NM_001029896.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.58

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: Benign. The variant received -16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001029896.2

BP4

Computational evidence support a benign effect (MetaRNN=0.17557627).

BP6

Variant X-49075704-T-C is Benign according to our data. Variant chrX-49075704-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 568990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000144 (16/111229) while in subpopulation NFE AF = 0.000246 (13/52950). AF 95% confidence interval is 0.000144. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High AC in GnomAd4 at 16 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR45	NM_001029896.2 link	c.566A>G	p.Asn189Ser	missense_variant	Exon 8 of 11	ENST00000376372.9	NP_001025067.1	Q9Y484-1A0A024QYX1
WDR45	NM_007075.4 link	c.569A>G	p.Asn190Ser	missense_variant	Exon 9 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.566A>G	p.Asn189Ser	missense_variant	Exon 8 of 11	1	NM_001029896.2	ENSP00000365551.3		Q9Y484-1
ENSG00000288053	ENST00000376358.4 link	c.260A>G	p.Asn87Ser	missense_variant	Exon 5 of 8	2		ENSP00000365536.3		A6NM71

Frequencies

GnomAD3 genomes

AF:

0.000144

AC:

AN:

111229

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000981

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:

0.000246

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000105

AC:

AN:

180572

AF XY:

0.000123

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000224

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000172

AC:

189

AN:

1097430

Hom.:

Cov.:

AF XY:

0.000185

AC XY:

AN XY:

362804

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26396

American (AMR)

AF:

0.00

AC:

AN:

35107

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19371

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30191

South Asian (SAS)

AF:

0.0000371

AC:

AN:

53960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.000210

AC:

177

AN:

841729

Other (OTH)

AF:

0.000130

AC:

AN:

46063

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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

AF:

0.000144

AC:

AN:

111229

Hom.:

Cov.:

AF XY:

0.0000896

AC XY:

AN XY:

33497

show subpopulations

African (AFR)

AF:

0.0000981

AC:

AN:

30579

American (AMR)

AF:

0.00

AC:

AN:

10405

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3534

South Asian (SAS)

AF:

0.00

AC:

AN:

2662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000246

AC:

AN:

52950

Other (OTH)

AF:

0.00

AC:

AN:

1494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000989

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Apr 08, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Neurodegeneration with brain iron accumulation 5

Benign:1

Nov 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 23, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.019

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

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

D;.;D;D;D;D;D;D;.;D;D;D;D;D;T;T;D

M_CAP

Benign

0.077

MetaRNN

Benign

0.18

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.51

.;N;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

7.6

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.2

N;N;.;.;.;.;.;N;N;N;N;N;.;.;.;N;.

REVEL

Benign

0.082

Sift

Benign

0.73

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

Sift4G

Benign

0.44

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

Polyphen

0.14

B;B;.;B;.;.;.;B;B;B;B;B;.;.;.;.;.

Vest4

0.52

MVP

0.49

MPC

1.2

ClinPred

0.074

GERP RS

3.8

PromoterAI

0.019

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.27

Mutation Taster

=98/2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over