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

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

KIAA0586
NM_001329943.3 splice_region, synonymous

Scores

2
Splicing: ADA: 0.9999
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.43
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 14-58482712-G-A is Pathogenic according to our data. Variant chr14-58482712-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KIAA0586NM_001329943.3 linkuse as main transcriptc.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
KIAA0586ENST00000652326.2 linkuse as main transcriptc.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:
5
AN:
205132
Hom.:
0
AF XY:
0.00000892
AC XY:
1
AN XY:
112120
show subpopulations
Gnomad AFR exome
AF:
0.0000722
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000205
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000491
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000863
AC:
12
AN:
1390920
Hom.:
0
Cov.:
30
AF XY:
0.00000436
AC XY:
3
AN XY:
687852
show subpopulations
Gnomad4 AFR exome
AF:
0.0000330
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000533
Gnomad4 SAS exome
AF:
0.0000261
Gnomad4 FIN exome
AF:
0.0000193
Gnomad4 NFE exome
AF:
0.00000372
Gnomad4 OTH exome
AF:
0.0000175
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Joubert syndrome 23 Pathogenic:1
Pathogenic, criteria provided, single submitterresearchUW Hindbrain Malformation Research Program, University of WashingtonSep 01, 2015- -
Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 14, 2023This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.77
CADD
Benign
18
DANN
Benign
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.79
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.79
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs540255320; hg19: chr14-58949430; COSMIC: COSV54174204; API