Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_001029896.2(WDR45):c.1030A>G(p.Asn344Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 24)

Consequence

WDR45
NM_001029896.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.25

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-49074856-T-C is Pathogenic according to our data. Variant chrX-49074856-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 212591.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001029896.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR45	NM_001029896.2	MANE Select	c.1030A>G	p.Asn344Asp	missense	Exon 11 of 11	NP_001025067.1
	WDR45	NM_007075.4		c.1033A>G	p.Asn345Asp	missense	Exon 12 of 12	NP_009006.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WDR45	ENST00000376372.9	TSL:1 MANE Select	c.1030A>G	p.Asn344Asp	missense	Exon 11 of 11	ENSP00000365551.3
WDR45	ENST00000356463.7	TSL:1	c.1033A>G	p.Asn345Asp	missense	Exon 12 of 12	ENSP00000348848.3
WDR45	ENST00000376368.7	TSL:1	c.1033A>G	p.Asn345Asp	missense	Exon 11 of 11	ENSP00000365546.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodegeneration with brain iron accumulation 5 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.9

PhyloP100

7.3

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.40

Sift

Benign

0.16

Sift4G

Benign

0.34

Polyphen

0.029

Vest4

0.56

MutPred

0.54

Loss of sheet (P = 0.007)

MVP

0.51

MPC

0.96

ClinPred

0.96

GERP RS

5.0

Varity_R

0.72

gMVP

0.87

Mutation Taster

=87/13

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over