Variant 14-58448363-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PP5_ModerateBP4BP7

The NM_001329943.3(KIAA0586):c.831C>T(p.Leu277=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000968 in 1,445,542 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 (★). Synonymous variant affecting the same amino acid position (i.e. L277L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

KIAA0586
NM_001329943.3 synonymous

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.383

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-58448363-C-T is Pathogenic according to our data. Variant chr14-58448363-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 475455.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-58448363-C-T is described in Lovd as [Pathogenic]. Variant chr14-58448363-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65). . Strength limited to SUPPORTING due to the PP5.

BP7

Synonymous conserved (PhyloP=0.383 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0586	NM_001329943.3 linkuse as main transcript	c.831C>T	p.Leu277=	synonymous_variant	7/31	ENST00000652326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0586	ENST00000652326.2 linkuse as main transcript	c.831C>T	p.Leu277=	synonymous_variant	7/31		NM_001329943.3	P4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000285

AC:

AN:

245872

Hom.:

AF XY:

0.0000450

AC XY:

AN XY:

133392

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:

0.0000625

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000968

AC:

AN:

1445542

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

719836

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000127

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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 05, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this silent change causes aberrant splicing, resulting in the loss of exon 9 and a frameshift in the mRNA (PMID: 26386044). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with features of asphyxiating thoracic dystrophy (Jeune syndrome) and Joubert syndrome (PMID: 26386044), and in combination with another rare variant in an individual affected with Joubert syndrome (PMID: 28497568). In addition, this variant has been observed to segregate with Joubert syndrome in a family (Invitae). This variant is present in population databases (rs780520735, ExAC 0.005%). This sequence change affects codon 330 of the KIAA0586 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the KIAA0586 protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

8.3

DANN

Benign

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

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