X-49075271-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001029896.2(WDR45):c.838G>A(p.Val280Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,209,412 control chromosomes in the GnomAD database, including 51 homozygotes. There are 829 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0067 ( 18 hom., 288 hem., cov: 24)

Exomes 𝑓: 0.0018 ( 33 hom. 541 hem. )

Consequence

WDR45
NM_001029896.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.26

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005992919).

BP6

Variant X-49075271-C-T is Benign according to our data. Variant chrX-49075271-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 282969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49075271-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR45	NM_001029896.2 linkuse as main transcript	c.838G>A	p.Val280Met	missense_variant	10/11	ENST00000376372.9
WDR45	NM_007075.4 linkuse as main transcript	c.841G>A	p.Val281Met	missense_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR45	ENST00000376372.9 linkuse as main transcript	c.838G>A	p.Val280Met	missense_variant	10/11	1	NM_001029896.2	P4	Q9Y484-1

Frequencies

GnomAD3 genomes

AF:

0.00672

AC:

755

AN:

112294

Hom.:

Cov.:

AF XY:

0.00829

AC XY:

286

AN XY:

34496

show subpopulations

Gnomad AFR

AF:

0.00129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0623

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00364

Gnomad SAS

AF:

0.000370

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000245

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.00670

AC:

1209

AN:

180428

Hom.:

AF XY:

0.00491

AC XY:

322

AN XY:

65530

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.0394

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00414

Gnomad SAS exome

AF:

0.000531

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000112

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.00178

AC:

1957

AN:

1097065

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

541

AN XY:

362495

show subpopulations

Gnomad4 AFR exome

AF:

0.000872

Gnomad4 AMR exome

AF:

0.0446

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00282

Gnomad4 SAS exome

AF:

0.000500

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000915

Gnomad4 OTH exome

AF:

0.00389

GnomAD4 genome

AF:

0.00675

AC:

758

AN:

112347

Hom.:

Cov.:

AF XY:

0.00833

AC XY:

288

AN XY:

34559

show subpopulations

Gnomad4 AFR

AF:

0.00129

Gnomad4 AMR

AF:

0.0625

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00365

Gnomad4 SAS

AF:

0.000371

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000245

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.000877

Hom.:

Bravo

AF:

0.0108

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.00349

AC:

424

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 23, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 06, 2015	- -

Neurodegeneration with brain iron accumulation 5;C3808786:Oculocutaneous albinism type 7

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 30, 2021

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2016

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.26

Cadd

Benign

Dann

Benign

0.92

DEOGEN2

Benign

0.041

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

FATHMM_MKL

Uncertain

0.87

MetaRNN

Benign

0.0060

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

MetaSVM

Benign

-0.88

MutationAssessor

Benign

-0.070

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.50

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

REVEL

Uncertain

0.30

Sift

Benign

0.61

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

Sift4G

Benign

0.59

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

Polyphen

0.027

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

Vest4

0.28

MVP

0.60

MPC

0.62

ClinPred

0.021

GERP RS

4.1

Varity_R

0.27

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over