X-49075704-T-C

Position:

chrX-49075704-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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 -18 ACMG points.

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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR45	NM_001029896.2 linkuse as main transcript	c.566A>G	p.Asn189Ser	missense_variant	8/11	ENST00000376372.9	NP_001025067.1
WDR45	NM_007075.4 linkuse as main transcript	c.569A>G	p.Asn190Ser	missense_variant	9/12		NP_009006.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR45	ENST00000376372.9 linkuse as main transcript	c.566A>G	p.Asn189Ser	missense_variant	8/11	1	NM_001029896.2	ENSP00000365551	P4	Q9Y484-1

Frequencies

GnomAD3 genomes

AF:

0.000144

AC:

AN:

111229

Hom.:

Cov.:

AF XY:

0.0000896

AC XY:

AN XY:

33497

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

GnomAD3 exomes

AF:

0.000105

AC:

AN:

180572

Hom.:

AF XY:

0.000123

AC XY:

AN XY:

65150

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 SAS exome

AF:

0.0000536

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

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000371

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000210

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.000144

AC:

AN:

111229

Hom.:

Cov.:

AF XY:

0.0000896

AC XY:

AN XY:

33497

show subpopulations

Gnomad4 AFR

AF:

0.0000981

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:

0.000246

Gnomad4 OTH

AF:

0.00

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2022

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 23, 2021

- -

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

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;.;.;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

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

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.27

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

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