4-39205626-T-TA
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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
NM_025132.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.06
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]
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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: {Pathogenic=4, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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WDR19 | NM_025132.4 | 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 | c.781dup | p.Thr261AsnfsTer13 | frameshift_variant | 9/37 | 1 | NM_025132.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152194Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000363 AC: 9AN: 248048Hom.: 0 AF XY: 0.0000446 AC XY: 6AN XY: 134510
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GnomAD4 exome AF: 0.000111 AC: 162AN: 1461112Hom.: 0 Cov.: 30 AF XY: 0.000113 AC XY: 82AN XY: 726726
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
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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-Løken 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
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