14-58427638-G-A

Position:

• chr14-58427638-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001244189.2(KIAA0586):​c.9+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,383,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: KIAA0586 NM_001244189.2 splice_donor, intron
• Scores: Splicing: ADA: 0.00001460
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: -0.393

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-58427638-G-A is Pathogenic according to our data. Variant chr14-58427638-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 992350.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIAA0586	NM_001244189.2	c.9+1G>A		splice_donor_variant, intron_variant			NP_001231118.1
KIAA0586	NM_001244190.2	c.-39+1G>A		splice_donor_variant, intron_variant			NP_001231119.1
KIAA0586	NM_001244192.2	c.-57+1G>A		splice_donor_variant, intron_variant			NP_001231121.1
KIAA0586	NM_001244191.2	c.-57+1G>A		splice_donor_variant, intron_variant			NP_001231120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIAA0586	ENST00000619416.4	c.-39+1G>A		splice_donor_variant, intron_variant		1		ENSP00000478083.1
KIAA0586	ENST00000423743.7	c.-57+1G>A		splice_donor_variant, intron_variant		1		ENSP00000399427.3
KIAA0586	ENST00000354386.10	c.9+1G>A		splice_donor_variant, intron_variant		2		ENSP00000346359.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000155 AC: 2 AN: 129236 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 70736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000821

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000434 AC: 6 AN: 1383364 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 682576

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000840

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000299

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2024	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published in association with a KIAA0586-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 36651276) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 18, 2020	- -

Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

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 sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 992350). This variant has not been reported in the literature in individuals affected with KIAA0586-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.008%). This sequence change affects a donor splice site in intron 1 of the KIAA0586 gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.27
DANN	Benign	0.86
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.020	N
MutationTaster	Benign	0.97	N;N;N
GERP RS		-8.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1490434047; hg19: chr14-58894356;