15-84643475-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032856.5(WDR73):c.1132C>T(p.Arg378Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000251 in 1,551,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R378H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

WDR73
NM_032856.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -1.55

Variant links:

Genes affected

WDR73 (HGNC:25928): (WD repeat domain 73) The protein encoded by this gene is thought to contain multiple WD40 repeats. WD40 repeats are motifs that contain 40-60 amino acids, and usually end with Trp-Asp (WD). This protein is found in the cytoplasm during interphase, but accumulates at the spindle poles and astral microtubules during mitosis. Reduced expression of this gene results in abnormalities in the size and morphology of the nucleus. Mutations in this gene have been associated with Galloway-Mowat syndrome PMID: 25466283), which is a rare autosomal recessive disorder that affects both the central nervous system and kidneys. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

WDR73 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046559393).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR73	NM_032856.5 linkuse as main transcript	c.1132C>T	p.Arg378Cys	missense_variant	8/8	ENST00000434634.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR73	ENST00000434634.7 linkuse as main transcript	c.1132C>T	p.Arg378Cys	missense_variant	8/8	1	NM_032856.5	P1
	ENST00000348993.9 linkuse as main transcript	n.4972G>A		non_coding_transcript_exon_variant	4/4	1

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151698

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000310

AC:

AN:

161158

Hom.:

AF XY:

0.0000352

AC XY:

AN XY:

85302

show subpopulations

Gnomad AFR exome

AF:

0.000115

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000866

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000318

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000222

AC:

AN:

1399542

Hom.:

Cov.:

AF XY:

0.0000217

AC XY:

AN XY:

690748

show subpopulations

Gnomad4 AFR exome

AF:

0.000157

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000378

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000176

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.0000527

AC:

AN:

151816

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000194

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000260

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galloway-Mowat syndrome 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 07, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 15, 2022	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 378 of the WDR73 protein (p.Arg378Cys). This variant is present in population databases (rs376622127, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with WDR73-related conditions. ClinVar contains an entry for this variant (Variation ID: 1031002). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.58

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.0018

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.44

M_CAP

Benign

0.038

MetaRNN

Benign

0.047

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.77

REVEL

Benign

0.087

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.076

MutPred

0.57

Gain of catalytic residue at P377 (P = 0.0039);

MVP

0.088

MPC

0.12

ClinPred

0.14

GERP RS

-12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.080

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

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