rs540255320
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001329943.3(KIAA0586):c.3144G>A(p.Pro1048=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000863 in 1,390,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001329943.3 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KIAA0586 | NM_001329943.3 | c.3144G>A | p.Pro1048= | splice_region_variant, synonymous_variant | 21/31 | ENST00000652326.2 | NP_001316872.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KIAA0586 | ENST00000652326.2 | c.3144G>A | p.Pro1048= | splice_region_variant, synonymous_variant | 21/31 | NM_001329943.3 | ENSP00000498929 | P4 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.0000244 AC: 5AN: 205132Hom.: 0 AF XY: 0.00000892 AC XY: 1AN XY: 112120
GnomAD4 exome AF: 0.00000863 AC: 12AN: 1390920Hom.: 0 Cov.: 30 AF XY: 0.00000436 AC XY: 3AN XY: 687852
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Joubert syndrome 23 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Sep 01, 2015 | - - |
Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 14, 2023 | This sequence change affects codon 1101 of the KIAA0586 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the KIAA0586 protein. This variant also falls at the last nucleotide of exon 23, which is part of the consensus splice site for this exon. This variant is present in population databases (rs540255320, gnomAD 0.02%). This variant has been observed in individual(s) with Joubert syndrome (PMID: 26096313; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 217667). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects KIAA0586 function (PMID: 2609613). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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