chr14-58427632-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The ENST00000619416.4(KIAA0586):c.-44T>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 0.00000391 in 1,535,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000022 ( 0 hom. )
Consequence
KIAA0586
ENST00000619416.4 5_prime_UTR
ENST00000619416.4 5_prime_UTR
Scores
1
1
13
Clinical Significance
Conservation
PhyloP100: -0.267
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 Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.11914095).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIAA0586 | NM_001244189.2 | c.4T>C | p.Phe2Leu | missense_variant | 1/34 | ||
KIAA0586 | NM_001244190.2 | c.-44T>C | 5_prime_UTR_variant | 1/32 | |||
KIAA0586 | NM_001244191.2 | c.-62T>C | 5_prime_UTR_variant | 1/31 | |||
KIAA0586 | NM_001244192.2 | c.-62T>C | 5_prime_UTR_variant | 1/32 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIAA0586 | ENST00000423743.7 | c.-62T>C | 5_prime_UTR_variant | 1/32 | 1 | ||||
KIAA0586 | ENST00000619416.4 | c.-44T>C | 5_prime_UTR_variant | 1/32 | 1 | A2 | |||
KIAA0586 | ENST00000354386.10 | c.4T>C | p.Phe2Leu | missense_variant | 1/34 | 2 | |||
KIAA0586 | ENST00000619722.5 | c.-62T>C | 5_prime_UTR_variant | 1/31 | 2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152084Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000217 AC: 3AN: 1383342Hom.: 0 Cov.: 30 AF XY: 0.00000293 AC XY: 2AN XY: 682566
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74296
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 11, 2021 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with KIAA0586-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces phenylalanine with leucine at codon 2 of the KIAA0586 protein (p.Phe2Leu). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and leucine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Pathogenic
D
Vest4
MutPred
Loss of catalytic residue at F2 (P = 0.0474);
MVP
MPC
ClinPred
T
GERP RS
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at