rs16995209

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_025132.4(WDR19):c.3250G>A(p.Gly1084Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00622 in 1,562,844 control chromosomes in the GnomAD database, including 496 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1084V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.033 ( 262 hom., cov: 31)

Exomes 𝑓: 0.0033 ( 234 hom. )

Consequence

WDR19
NM_025132.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 9.27

Variant links:

Genes affected

WDR19 (HGNC:18340): (WD repeat domain 19) The protein encoded by this gene is a member of the WD (tryptophan-aspartic acid) repeat family, which is a large family of structurally-related proteins known to participate in a wide range of cellular processes. Each WD repeat typically contains about 40 amino acids that are usually bracketed by glycine-histidine and tryptophan-aspartic acid (WD) dipeptides. This protein contains six WD repeats, three transmembrane domains, and a clathrin heavy-chain repeat. Mutations in this gene have been described in individuals with a wide range of disorders affecting function of the cilium. These disorders are known as ciliopathies, and include Jeune syndrome, Sensenbrenner syndromes, Senior-Loken syndrome, combined or isolated nephronophthisis (NPHP), and retinitis pigmentosa (RP). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

WDR19 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032558143).

BP6

Variant 4-39266129-G-A is Benign according to our data. Variant chr4-39266129-G-A is described in ClinVar as [Benign]. Clinvar id is 261863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-39266129-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR19	NM_025132.4 linkuse as main transcript	c.3250G>A	p.Gly1084Ser	missense_variant	29/37	ENST00000399820.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR19	ENST00000399820.8 linkuse as main transcript	c.3250G>A	p.Gly1084Ser	missense_variant	29/37	1	NM_025132.4	P1	Q8NEZ3-1
WDR19	ENST00000512095.5 linkuse as main transcript	n.2248G>A		non_coding_transcript_exon_variant	19/23	2
WDR19	ENST00000506869.5 linkuse as main transcript	c.*2831G>A		3_prime_UTR_variant, NMD_transcript_variant	28/36	2

Frequencies

GnomAD3 genomes

AF:

0.0329

AC:

5005

AN:

152114

Hom.:

261

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0123

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.0244

GnomAD3 exomes

AF:

0.00778

AC:

1366

AN:

175504

Hom.:

AF XY:

0.00596

AC XY:

553

AN XY:

92842

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.00578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000863

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000453

Gnomad OTH exome

AF:

0.00620

GnomAD4 exome

AF:

0.00334

AC:

4716

AN:

1410612

Hom.:

234

Cov.:

AF XY:

0.00295

AC XY:

2056

AN XY:

696588

show subpopulations

Gnomad4 AFR exome

AF:

0.115

Gnomad4 AMR exome

AF:

0.00674

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000163

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000310

Gnomad4 OTH exome

AF:

0.00700

GnomAD4 genome

AF:

0.0329

AC:

5010

AN:

152232

Hom.:

262

Cov.:

AF XY:

0.0316

AC XY:

2356

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.114

Gnomad4 AMR

AF:

0.0123

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.0242

Alfa

AF:

0.00626

Hom.:

Bravo

AF:

0.0376

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.104

AC:

417

ESP6500EA

AF:

0.000360

AC:

ExAC

AF:

0.00723

AC:

843

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Asphyxiating thoracic dystrophy 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

Cranioectodermal dysplasia 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Nephronophthisis 13

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Senior-Loken syndrome 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 22, 2022

- -

Asphyxiating thoracic dystrophy 5;C4225376:Senior-Loken syndrome 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.13

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.67

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0033

MetaSVM

Benign

-0.72

MutationAssessor

Pathogenic

3.2

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.42

Sift

Uncertain

0.017

Sift4G

Uncertain

0.0090

Polyphen

0.77

Vest4

0.78

MVP

0.77

MPC

0.45

ClinPred

0.080

GERP RS

5.4

Varity_R

0.62

gMVP

0.70

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