chr14-58428236-A-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_001329943.3(KIAA0586):c.-29A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000619 in 1,452,880 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000062 ( 1 hom. )
Consequence
KIAA0586
NM_001329943.3 5_prime_UTR
NM_001329943.3 5_prime_UTR
Scores
1
6
Splicing: ADA: 0.0003559
2
Clinical Significance
Conservation
PhyloP100: 1.29
Genes affected
KIAA0586 (HGNC:19960): (KIAA0586) This gene encodes a conserved centrosomal protein that functions in ciliogenesis and responds to hedgehog signaling. Mutations in this gene causes Joubert syndrome 23. Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 14-58428236-A-C is Pathogenic according to our data. Variant chr14-58428236-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 424017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
?
Computational evidence support a benign effect (BayesDel_addAF=-0.367222).. Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIAA0586 | NM_001329943.3 | c.-29A>C | 5_prime_UTR_variant | 1/31 | ENST00000652326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIAA0586 | ENST00000652326.2 | c.-29A>C | 5_prime_UTR_variant | 1/31 | NM_001329943.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000423 AC: 1AN: 236292Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 128036
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GnomAD4 exome AF: 0.00000619 AC: 9AN: 1452880Hom.: 1 Cov.: 32 AF XY: 0.00000831 AC XY: 6AN XY: 722088
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GnomAD4 genome ? Cov.: 32
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32
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1
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2023 | 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; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge - |
Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 424017). This variant has not been reported in the literature in individuals affected with KIAA0586-related conditions. This variant is present in population databases (rs752709426, gnomAD 0.006%). This sequence change affects an acceptor splice site in intron 1 of the KIAA0586 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 KIAA0586 are known to be pathogenic (PMID: 26096313, 26166481, 26386044). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
D;D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at