rs587777352
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_025132.4(WDR19):c.3565+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,599,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_025132.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WDR19 | ENST00000399820.8 | c.3565+1G>A | splice_donor_variant, intron_variant | Intron 32 of 36 | 1 | NM_025132.4 | ENSP00000382717.3 | |||
WDR19 | ENST00000512534.5 | n.131G>A | non_coding_transcript_exon_variant | Exon 2 of 6 | 2 | |||||
WDR19 | ENST00000506869.5 | n.*3146+1G>A | splice_donor_variant, intron_variant | Intron 31 of 35 | 2 | ENSP00000424319.1 | ||||
WDR19 | ENST00000512095.5 | n.2563+1G>A | splice_donor_variant, intron_variant | Intron 22 of 22 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152108Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000264 AC: 6AN: 227094Hom.: 0 AF XY: 0.00000819 AC XY: 1AN XY: 122038
GnomAD4 exome AF: 0.000115 AC: 167AN: 1447632Hom.: 0 Cov.: 30 AF XY: 0.000110 AC XY: 79AN XY: 718428
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74304
ClinVar
Submissions by phenotype
Senior-Loken syndrome 8 Pathogenic:2
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not provided Pathogenic:2
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Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29121203, 23559409, 30586318, 26489029, 29068549) -
Jeune thoracic dystrophy Pathogenic:2
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Nephronophthisis 13 Pathogenic:1
Variant summary: WDR19 c.3565+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.6e-05 in 227094 control chromosomes. c.3565+1G>A has been reported in the literature as a compound heterozygous genotype in comprehensively analyzed individuals with nephronophthisis-related ciliopathy and/or skeletal ciliopathies such as asphyxiating thoracic dystrophy (ATD) (example, Halbritter_2013, Braun_2016, Zhang_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Connective tissue disorder Pathogenic:1
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Asphyxiating thoracic dystrophy 5;C4225376:Senior-Loken syndrome 8 Pathogenic:1
This sequence change affects a donor splice site in intron 32 of the WDR19 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in WDR19 are known to be pathogenic (PMID: 22019273, 23559409, 23683095, 26275793, 27241786, 29068549). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with ciliopathy disorders (PMID: 23559409, 29068549). ClinVar contains an entry for this variant (Variation ID: 127159). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at