rs757350052

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong

The NM_001329943.3(KIAA0586):c.1254-1G>C variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,564,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

KIAA0586
NM_001329943.3 splice_acceptor

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.613

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]

KIAA0586 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 22 ACMG points.

PVS1

Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.8, offset of 17, new splice context is: aacatttccttcctgtgaAGagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP3

BayesDel_addAF computational evidence supports a deleterious effect, 0.437

PP5

Variant 14-58456701-G-C is Pathogenic according to our data. Variant chr14-58456701-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 204594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0586	NM_001329943.3 linkuse as main transcript	c.1254-1G>C		splice_acceptor_variant		ENST00000652326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0586	ENST00000652326.2 linkuse as main transcript	c.1254-1G>C		splice_acceptor_variant			NM_001329943.3	P4

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000682

AC:

AN:

219932

Hom.:

AF XY:

0.0000844

AC XY:

AN XY:

118502

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000118

AC:

166

AN:

1412474

Hom.:

Cov.:

AF XY:

0.0000953

AC XY:

AN XY:

702998

show subpopulations

Gnomad4 AFR exome

AF:

0.0000311

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000146

Gnomad4 OTH exome

AF:

0.000136

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Joubert syndrome 23

Pathogenic:5

Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Sep 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Aug 28, 2019	A heterozygous canonical splice site variant was identified, NM_001244189.1(KIAA0586):c.1413-1G>C in intron 11 of the KIAA0586 gene. RNA studies have shown this substitution causes a frameshift from amino acid position 472 introducing a stop codon 2 residues downstream, NP_001231118.1(KIAA0586):p.(Arg472Serfs*2) resulting in loss of normal protein function through nonsense-mediated decay (NMD). The nucleotide at this position has low conservation (Phylop UCSC). In silico software predicts the splice site variant to cause aberrant splicing (NetGene2, Fruit fly, Human Splicing Finder). The variant is present in the gnomAD population database at a frequency of 0.0068% (15 heterozygotes, 0 homozygotes). It has been previously reported in patients with Joubert syndrome (ClinVar; Decipher; Roosing, S. et al., 2015; Bachmann-Gagescu, R. et al., 2015; Malicdan, M.C. et al., 2015). The variant has also been previously reported pathogenic in trans with p.(Arg309Ser) in a patient with Duane anomaly, macrocephaly, global developmental delay and molar tooth sign (Decipher). It has also been shown to segregate with the disease in one family (Roosing, S. et al., 2015). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 03, 2020	ACMG codes:PVS1, PM2, PM3, PP5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 11, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 02, 2022	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2021	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that this variant leads to utilization of a cryptic splice acceptor site, resulting in an aberrant transcript and absent protein levels in patient fibroblasts (Roosing et al., 2015); This variant is associated with the following publications: (PMID: 26437029, 26026149, 26096313, 28497568, 30120217, 26386044, 27535533) -

Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 03, 2023

This sequence change affects an acceptor splice site in intron 11 of the KIAA0586 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs757350052, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with Joubert syndrome (PMID: 26026149, 26096313, 26386044, 26437029, 28497568). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1209-1G>C or c.1254-1G>C. ClinVar contains an entry for this variant (Variation ID: 204594). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 26026149). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Benign

-0.52

Cadd

Benign

Dann

Benign

0.81

Eigen

Uncertain

0.45

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.064

MutationTaster

Benign

1.0

D;D;D;D

GERP RS

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.69

SpliceAI score (max)

0.61

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.21

Position offset: 18

DS_AL_spliceai

0.61

Position offset: 1

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over