rs762081862

Positions:

• chr14-58458545-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001329943.3(KIAA0586):​c.1656G>A​(p.Gln552Gln) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000881 in 1,362,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000088 (0 hom.)
• Consequence: KIAA0586 NM_001329943.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.8679
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.54

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-58458545-G-A is Pathogenic according to our data. Variant chr14-58458545-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208813.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
KIAA0586	NM_001329943.3	c.1656G>A	p.Gln552Gln	splice_region_variant, synonymous_variant	12/31	ENST00000652326.2	NP_001316872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIAA0586	ENST00000652326.2	c.1656G>A	p.Gln552Gln	splice_region_variant, synonymous_variant	12/31		NM_001329943.3	ENSP00000498929.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000138 AC: 2 AN: 144934 Hom.: 0 AF XY: 0.0000131 AC XY: 1 AN XY: 76502

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000476

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: 0.0000173

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000881 AC: 12 AN: 1362244 Hom.: 0 Cov.: 23 AF XY: 0.0000104 AC XY: 7 AN XY: 672654

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000304

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: 0.00000949

Gnomad4 OTH exome AF: 0.0000177

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Short-rib thoracic dysplasia 14 with polydactyly Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 27, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 06, 2015	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

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

Sep 21, 2022

This sequence change affects codon 605 of the KIAA0586 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the KIAA0586 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs762081862, gnomAD 0.005%). This variant has been observed in individuals with short-rib thoracic dysplasia (PMID: 2080096, 26166481). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208813). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 14 skipping and introduces a premature termination codon (PMID: 26166481). 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_noAF	Benign	-0.31
CADD	Benign	20
DANN	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.87
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs762081862; hg19: chr14-58925263;