rs199783864

Variant summary

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

The NM_025132.4(WDR19):ā€‹c.929A>Gā€‹(p.Tyr310Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000303 in 1,586,570 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00029 ( 0 hom., cov: 32)
Exomes š‘“: 0.00030 ( 1 hom. )

Consequence

WDR19
NM_025132.4 missense

Scores

2
13
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 6.72
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WDR19NM_025132.4 linkuse as main transcriptc.929A>G p.Tyr310Cys missense_variant 10/37 ENST00000399820.8 NP_079408.3 Q8NEZ3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WDR19ENST00000399820.8 linkuse as main transcriptc.929A>G p.Tyr310Cys missense_variant 10/371 NM_025132.4 ENSP00000382717.3 Q8NEZ3-1

Frequencies

GnomAD3 genomes
AF:
0.000289
AC:
44
AN:
152120
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000280
AC:
67
AN:
239004
Hom.:
0
AF XY:
0.000263
AC XY:
34
AN XY:
129404
show subpopulations
Gnomad AFR exome
AF:
0.0000656
Gnomad AMR exome
AF:
0.0000313
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000560
Gnomad NFE exome
AF:
0.000481
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000305
AC:
437
AN:
1434450
Hom.:
1
Cov.:
27
AF XY:
0.000293
AC XY:
209
AN XY:
713142
show subpopulations
Gnomad4 AFR exome
AF:
0.0000920
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000584
Gnomad4 NFE exome
AF:
0.000348
Gnomad4 OTH exome
AF:
0.000370
GnomAD4 genome
AF:
0.000289
AC:
44
AN:
152120
Hom.:
0
Cov.:
32
AF XY:
0.000269
AC XY:
20
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000189
Gnomad4 NFE
AF:
0.000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000374
Hom.:
0
Bravo
AF:
0.000170
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000246
AC:
2
ExAC
AF:
0.000414
AC:
50

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 26, 2018The WDR19 variant (rs199783864), to our knowledge, is not described in the medical literature but contains an entry in ClinVar (Variation ID: 348727). It is observed in the general population at an overall frequency of 0.03% (83/267358 alleles) in the Genome Aggregation Database. The tyrosine at codon 310 is moderately conserved, but computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. Due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 26, 2022The c.929A>G (p.Y310C) alteration is located in exon 10 (coding exon 10) of the WDR19 gene. This alteration results from a A to G substitution at nucleotide position 929, causing the tyrosine (Y) at amino acid position 310 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Asphyxiating thoracic dystrophy 5;C3280612:Nephronophthisis 13;C3280616:Cranioectodermal dysplasia 4;C4225376:Senior-Loken syndrome 8;C5676980:Spermatogenic failure 72 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 11, 2022- -
Asphyxiating thoracic dystrophy 5 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Cranioectodermal dysplasia 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Asphyxiating thoracic dystrophy 5;C4225376:Senior-Loken syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 14, 2024This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 310 of the WDR19 protein (p.Tyr310Cys). This variant is present in population databases (rs199783864, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with WDR19-related conditions. ClinVar contains an entry for this variant (Variation ID: 348727). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WDR19 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
0.083
BayesDel_addAF
Uncertain
0.022
T
BayesDel_noAF
Pathogenic
0.20
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.44
T;.
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Uncertain
0.48
T;T
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Uncertain
2.2
M;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-2.9
D;D
REVEL
Uncertain
0.61
Sift
Benign
0.13
T;T
Sift4G
Benign
0.090
T;D
Polyphen
0.010
B;D
Vest4
0.61
MVP
0.97
MPC
0.22
ClinPred
0.084
T
GERP RS
5.5
Varity_R
0.20
gMVP
0.34

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.

Other links and lift over

dbSNP: rs199783864; hg19: chr4-39216259; API