Genetic Variant WDR90:p.Arg223Trp (chr16-651102-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_145294.5(WDR90):c.667C>T(p.Arg223Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,403,438 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000062 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000095 ( 0 hom. )

Consequence

WDR90
NM_145294.5 missense, splice_region

Scores

Splicing: ADA: 0.1228

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.40

Variant links:

Genes affected

WDR90 (HGNC:26960): (WD repeat domain 90) Involved in cilium assembly. Located in centriole. [provided by Alliance of Genome Resources, Apr 2022]

WDR90 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR90	NM_145294.5 link	c.667C>T	p.Arg223Trp	missense_variant, splice_region_variant	Exon 6 of 41	ENST00000293879.9	NP_660337.3	Q96KV7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR90	ENST00000293879.9 link	c.667C>T	p.Arg223Trp	missense_variant, splice_region_variant	Exon 6 of 41	5	NM_145294.5	ENSP00000293879.4		Q96KV7-1

Frequencies

GnomAD3 genomes

AF:

0.0000624

AC:

AN:

144242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000137

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:

0.0000306

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248754

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135210

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000953

AC:

AN:

1259196

Hom.:

Cov.:

AF XY:

0.00000957

AC XY:

AN XY:

626988

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000125

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000821

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000624

AC:

AN:

144242

Hom.:

Cov.:

AF XY:

0.0000855

AC XY:

AN XY:

70198

show subpopulations

Gnomad4 AFR

AF:

0.000124

Gnomad4 AMR

AF:

0.000137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000306

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.000240

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 07, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.667C>T (p.R223W) alteration is located in exon 6 (coding exon 6) of the WDR90 gene. This alteration results from a C to T substitution at nucleotide position 667, causing the arginine (R) at amino acid position 223 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.051

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.076

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.9

.;M

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Benign

0.26

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

.;D

Vest4

0.64

MVP

0.33

MPC

0.56

ClinPred

0.86

GERP RS

2.8

Varity_R

0.28

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.12

dbscSNV1_RF

Benign

0.19

SpliceAI score (max)

0.0

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