Genetic Variant WDR76:p.Arg190Cys (chr15-43836176-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024908.4(WDR76):c.568C>T(p.Arg190Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000616 in 1,606,614 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000061 ( 1 hom. )

Consequence

WDR76
NM_024908.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.10

Variant links:

Genes affected

WDR76 (HGNC:25773): (WD repeat domain 76) Enables enzyme binding activity. Involved in cellular response to DNA damage stimulus. Located in heterochromatin; nucleus; and site of DNA damage. [provided by Alliance of Genome Resources, Apr 2022]

WDR76 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16300702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR76	NM_024908.4 link	c.568C>T	p.Arg190Cys	missense_variant	Exon 4 of 13	ENST00000263795.11	NP_079184.2	Q9H967
WDR76	NM_001167941.2 link	c.376C>T	p.Arg126Cys	missense_variant	Exon 4 of 13		NP_001161413.1	Q9H967A0A0C4DFX7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WDR76	ENST00000263795.11 link	c.568C>T	p.Arg190Cys	missense_variant	Exon 4 of 13	1	NM_024908.4	ENSP00000263795.6	Q9H967
WDR76	ENST00000381246.6 link	c.376C>T	p.Arg126Cys	missense_variant	Exon 4 of 13	1		ENSP00000370645.2	A0A0C4DFX7
WDR76	ENST00000452115.1 link	c.376C>T	p.Arg126Cys	missense_variant	Exon 4 of 7	5		ENSP00000404665.1	C9JE56

Frequencies

GnomAD3 genomes

AF:

0.0000659

AC:

AN:

151746

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000809

AC:

AN:

247264

Hom.:

AF XY:

0.0000523

AC XY:

AN XY:

133782

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000334

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.000135

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000612

AC:

AN:

1454750

Hom.:

Cov.:

AF XY:

0.0000567

AC XY:

AN XY:

723374

show subpopulations

Gnomad4 AFR exome

AF:

0.0000901

Gnomad4 AMR exome

AF:

0.000274

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000523

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151864

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74196

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000213

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.568C>T (p.R190C) alteration is located in exon 4 (coding exon 4) of the WDR76 gene. This alteration results from a C to T substitution at nucleotide position 568, causing the arginine (R) at amino acid position 190 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.20

T;T;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.056

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.8

M;.;.

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Benign

0.27

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.32

MVP

0.73

MPC

0.59

ClinPred

0.33

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.35

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

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