dbSNP rs781979357: WDR45:p.Asp349His (chrX-49074841-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001029896.2(WDR45):c.1045G>C(p.Asp349His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

WDR45
NM_001029896.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.15

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:

ENSG00000288053 (HGNC:):

ENSG00000288053 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR45	NM_001029896.2 link	c.1045G>C	p.Asp349His	missense_variant	Exon 11 of 11	ENST00000376372.9	NP_001025067.1	Q9Y484-1A0A024QYX1
WDR45	NM_007075.4 link	c.1048G>C	p.Asp350His	missense_variant	Exon 12 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.1045G>C	p.Asp349His	missense_variant	Exon 11 of 11	1	NM_001029896.2	ENSP00000365551.3		Q9Y484-1
ENSG00000288053	ENST00000376358.4 link	c.521+523G>C		intron_variant	Intron 6 of 7	2		ENSP00000365536.3		A6NM71

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183494

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67928

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.11e-7

AC:

AN:

1097751

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363165

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

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

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.86

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

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.1

L;L;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-4.0

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

REVEL

Uncertain

0.61

Sift

Benign

0.060

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

Sift4G

Benign

0.14

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

Polyphen

0.26

B;B;.;.;.;D;D;D;D;.

Vest4

0.70

MutPred

0.58

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;.;.;.;.;.;.;

MVP

0.70

MPC

1.7

ClinPred

0.91

GERP RS

5.0

Varity_R

0.72

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over