chr14-58498952-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001329943.3(KIAA0586):c.4160C>T(p.Thr1387Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000763 in 1,598,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001329943.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIAA0586 | NM_001329943.3 | c.4160C>T | p.Thr1387Ile | missense_variant | 27/31 | ENST00000652326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIAA0586 | ENST00000652326.2 | c.4160C>T | p.Thr1387Ile | missense_variant | 27/31 | NM_001329943.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000454 AC: 69AN: 152128Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000136 AC: 31AN: 227282Hom.: 0 AF XY: 0.000138 AC XY: 17AN XY: 122816
GnomAD4 exome AF: 0.0000366 AC: 53AN: 1446392Hom.: 0 Cov.: 30 AF XY: 0.0000279 AC XY: 20AN XY: 718072
GnomAD4 genome AF: 0.000454 AC: 69AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.000458 AC XY: 34AN XY: 74308
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 02, 2022 | - - |
Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1440 of the KIAA0586 protein (p.Thr1440Ile). This variant is present in population databases (rs376795880, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with KIAA0586-related conditions. ClinVar contains an entry for this variant (Variation ID: 475452). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Joubert syndrome 23 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | May 17, 2023 | This KIAA0586 missense variant (rs376795880) is present in a large population dataset (gnomAD v3.1.2: 69/152128 total alleles; 0.045%; no homozygotes). It has been reported in ClinVar (Variation ID 475452), but has not been reported in the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be tolerated. While the threonine residue at this position is evolutionarily conserved across many of the species assessed, several species have a different amino acid at this position, including a few with isoleucine. We consider the clinical significance of c.4319C>T; p.Thr1440Ile in KIAA0586 to be uncertain at this time. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at