rs748656635

chr4-39205626-T-TA

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The NM_025132.4(WDR19):c.781dup(p.Thr261AsnfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,613,306 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

WDR19
NM_025132.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 1.06

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 Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 4-39205626-T-TA is Pathogenic according to our data. Variant chr4-39205626-T-TA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446634.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR19	NM_025132.4 linkuse as main transcript	c.781dup	p.Thr261AsnfsTer13	frameshift_variant	9/37	ENST00000399820.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR19	ENST00000399820.8 linkuse as main transcript	c.781dup	p.Thr261AsnfsTer13	frameshift_variant	9/37	1	NM_025132.4	P1	Q8NEZ3-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000363

AC:

AN:

248048

Hom.:

AF XY:

0.0000446

AC XY:

AN XY:

134510

show subpopulations

Gnomad AFR exome

AF:

0.0000648

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000712

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000111

AC:

162

AN:

1461112

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

726726

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.00

Gnomad4 NFE exome

AF:

0.000140

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Jeune thoracic dystrophy

Pathogenic:2

Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -

Nephronophthisis 13;C4225376:Senior-Loken syndrome 8

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 31, 2017

- -

Asphyxiating thoracic dystrophy 5

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 04, 2023

The p.Thr261AsnfsX13 variant in WDR19 has been reported in the compound heterozygous state with another WDR19 variant in at least 2 individuals with clinical features of WDR19-associated ciliopathies (including asphyxiating thoracic dystrophy and/or nephronophthisis). It was also reported in the heterozygous state in 3 individuals with clinical features consistent with WDR-19 associated ciliopathies where a second variant was not identified (Halbritter 2013 PMID: 23559409, Coussa 2013 PMID: 23683095, Meng 2017 PMID: 28973083, Zhang 2018 PMID: 29068549, Liu 2019 PMID: 31216405). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 446634) and has been identified in 0.007% (3/41448) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), at a frequency low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 261 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function variants in WDR19 gene have been reported in individuals with autosomal recessive ciliopathies (Bredrup 2011 PMID: 22019273, Zhang 2018 PMID: 29068549). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive WDR19-associated ciliopathies. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Supporting. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 18, 2022

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

This sequence change creates a premature translational stop signal (p.Thr261Asnfs*13) in the WDR19 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WDR19 are known to be pathogenic (PMID: 22019273, 23559409, 23683095, 26275793, 27241786, 29068549). This variant is present in population databases (rs748656635, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 28973083, 29068549). ClinVar contains an entry for this variant (Variation ID: 446634). For these reasons, this variant has been classified as Pathogenic. -

WDR19-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 16, 2018

The WDR19 c.781dupA (p.Thr261AsnfsTer13) frameshift variant has been reported in three studies, where it was found in a compound heterozygous state with a missense variant in one individual and in a heterozygous state in three individuals in whom a second variant was not identified (Halbritter et al. 2013; Coussa et al. 2013; Zhang et al. 2018). The compound heterozygous individual and two of the heterozygous individuals showed features of asphyxiating thoracic dystrophy; one of these heterozygotes also exhibited night blindness and was diagnosed with Senior-LÃ¸ken syndrome. The third heterozygous individual had isolated nephronophthisis. The p.Thr261AsnfsTer13 variant was absent from at least 192 healthy control subjects and is reported at a frequency of 0.000079 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies have not been conducted for the p.Thr261AsnfsTer13 variant, which occurs in the fifth WD40 repeat domain of the protein. Due to the limited evidence available and the potential impact of frameshift variants, the p.Thr261AsnfsTer13 variant is classified as a variant of unknown significance but suspicious for pathogenicity for WDR19-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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