rs75964850

Positions:

chr4-39214620-G-A

Variant summary

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

The NM_025132.4(WDR19):c.910G>A(p.Val304Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 1,564,718 control chromosomes in the GnomAD database, including 1,050 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 133 hom., cov: 32)

Exomes 𝑓: 0.034 ( 917 hom. )

Consequence

WDR19
NM_025132.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.242

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=0.0018529892).

BP6

Variant 4-39214620-G-A is Benign according to our data. Variant chr4-39214620-G-A is described in ClinVar as [Benign]. Clinvar id is 261868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-39214620-G-A is described in Lovd as [Benign]. Variant chr4-39214620-G-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR19	NM_025132.4 linkuse as main transcript	c.910G>A	p.Val304Ile	missense_variant	10/37	ENST00000399820.8	NP_079408.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR19	ENST00000399820.8 linkuse as main transcript	c.910G>A	p.Val304Ile	missense_variant	10/37	1	NM_025132.4	ENSP00000382717	P1	Q8NEZ3-1

Frequencies

GnomAD3 genomes

AF:

0.0391

AC:

5932

AN:

151886

Hom.:

133

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0428

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0309

Gnomad ASJ

AF:

0.0631

Gnomad EAS

AF:

0.0129

Gnomad SAS

AF:

0.0338

Gnomad FIN

AF:

0.0279

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0415

Gnomad OTH

AF:

0.0493

GnomAD3 exomes

AF:

0.0336

AC:

7829

AN:

232882

Hom.:

171

AF XY:

0.0336

AC XY:

4232

AN XY:

126122

show subpopulations

Gnomad AFR exome

AF:

0.0422

Gnomad AMR exome

AF:

0.0199

Gnomad ASJ exome

AF:

0.0646

Gnomad EAS exome

AF:

0.0112

Gnomad SAS exome

AF:

0.0268

Gnomad FIN exome

AF:

0.0251

Gnomad NFE exome

AF:

0.0400

Gnomad OTH exome

AF:

0.0395

GnomAD4 exome

AF:

0.0338

AC:

47715

AN:

1412714

Hom.:

917

Cov.:

AF XY:

0.0338

AC XY:

23752

AN XY:

702544

show subpopulations

Gnomad4 AFR exome

AF:

0.0360

Gnomad4 AMR exome

AF:

0.0210

Gnomad4 ASJ exome

AF:

0.0629

Gnomad4 EAS exome

AF:

0.00954

Gnomad4 SAS exome

AF:

0.0261

Gnomad4 FIN exome

AF:

0.0256

Gnomad4 NFE exome

AF:

0.0351

Gnomad4 OTH exome

AF:

0.0352

GnomAD4 genome

AF:

0.0391

AC:

5939

AN:

152004

Hom.:

133

Cov.:

AF XY:

0.0375

AC XY:

2786

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.0428

Gnomad4 AMR

AF:

0.0308

Gnomad4 ASJ

AF:

0.0631

Gnomad4 EAS

AF:

0.0129

Gnomad4 SAS

AF:

0.0340

Gnomad4 FIN

AF:

0.0279

Gnomad4 NFE

AF:

0.0416

Gnomad4 OTH

AF:

0.0483

Alfa

AF:

0.0420

Hom.:

235

Bravo

AF:

0.0390

TwinsUK

AF:

0.0402

AC:

149

ALSPAC

AF:

0.0402

AC:

155

ESP6500AA

AF:

0.0396

AC:

143

ESP6500EA

AF:

0.0435

AC:

354

ExAC

AF:

0.0342

AC:

4133

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	-	- -

Asphyxiating thoracic dystrophy 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Cranioectodermal dysplasia 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 17, 2022

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.098

T;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

0.55

N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.40

N;N

REVEL

Benign

0.11

Sift

Benign

0.26

T;T

Sift4G

Benign

0.092

T;T

Polyphen

0.0040

B;B

Vest4

0.094

MPC

0.15

ClinPred

0.0049

GERP RS

0.086

Varity_R

0.019

gMVP

0.097

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