chr15-84643481-C-T

Position:

chr15-84643481-C-T

Variant summary

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

The NM_032856.5(WDR73):c.1126G>A(p.Ala376Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000578 in 1,556,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. A376S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

WDR73
NM_032856.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.127

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:

ENSG00000291159 (HGNC:):

ENSG00000291159 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=0.054500192).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR73	NM_032856.5 linkuse as main transcript	c.1126G>A	p.Ala376Thr	missense_variant	8/8	ENST00000434634.7	NP_116245.2	Q6P4I2Q6PJL8Q5RKY8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR73	ENST00000434634.7 linkuse as main transcript	c.1126G>A	p.Ala376Thr	missense_variant	8/8	1	NM_032856.5	ENSP00000387982.3		Q6P4I2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000570

AC:

AN:

1404346

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

693224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000313

Gnomad4 AMR exome

AF:

0.0000278

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000251

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000277

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galloway-Mowat syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The observed missense c.1126G>A (p.Ala376Thr) variant in WDR73 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ala376Thr variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. The amino acid change p.Ala376Thr in WDR73 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 376 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). In absence of another reportable variant in WDR73 gene, the molecular diagnosis is not confirmed. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 18, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 376 of the WDR73 protein (p.Ala376Thr). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with WDR73-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The threonine 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

0.074

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0012

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.47

M_CAP

Benign

0.015

MetaRNN

Benign

0.055

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PrimateAI

Benign

0.32

PROVEAN

Benign

0.020

REVEL

Benign

0.0090

Sift

Benign

0.18

Sift4G

Benign

0.27

Polyphen

0.011

Vest4

0.023

MutPred

0.27

Gain of loop (P = 0.1069);

MVP

0.12

MPC

0.069

ClinPred

0.16

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.021

gMVP

0.25

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