chr14-58429365-T-A

Position:

chr14-58429365-T-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_001329943.3(KIAA0586):c.202T>A(p.Ser68Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000889 in 1,575,674 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00076 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 11 hom. )

Consequence

KIAA0586
NM_001329943.3 missense, splice_region

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.14

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 Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069651008).

BP6

Variant 14-58429365-T-A is Benign according to our data. Variant chr14-58429365-T-A is described in ClinVar as [Benign]. Clinvar id is 475443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000903 (1285/1423360) while in subpopulation EAS AF= 0.0112 (442/39346). AF 95% confidence interval is 0.0104. There are 11 homozygotes in gnomad4_exome. There are 757 alleles in male gnomad4_exome subpopulation. Median coverage is 26. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 11 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0586	NM_001329943.3 linkuse as main transcript	c.202T>A	p.Ser68Thr	missense_variant, splice_region_variant	2/31	ENST00000652326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0586	ENST00000652326.2 linkuse as main transcript	c.202T>A	p.Ser68Thr	missense_variant, splice_region_variant	2/31		NM_001329943.3	P4

Frequencies

GnomAD3 genomes

AF:

0.000756

AC:

115

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0106

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00185

AC:

461

AN:

248986

Hom.:

AF XY:

0.00199

AC XY:

269

AN XY:

135102

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0106

Gnomad SAS exome

AF:

0.00814

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000797

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.000903

AC:

1285

AN:

1423360

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

757

AN XY:

710658

show subpopulations

Gnomad4 AFR exome

AF:

0.0000612

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.0112

Gnomad4 SAS exome

AF:

0.00795

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000557

Gnomad4 OTH exome

AF:

0.00159

GnomAD4 genome

AF:

0.000755

AC:

115

AN:

152314

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0106

Gnomad4 SAS

AF:

0.0106

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000472

Hom.:

Bravo

AF:

0.000502

ExAC

AF:

0.00194

AC:

234

Asia WGS

AF:

0.0100

AC:

AN:

3474

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2020	This variant is associated with the following publications: (PMID: 30993914) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	KIAA0586: BP4, BS1, BS2 -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.059

.;T;.

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.55

T;T;T

MetaRNN

Benign

0.0070

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

.;M;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.67

N;.;N

REVEL

Benign

0.071

Sift

Benign

0.060

T;.;T

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.34

.;B;.

Vest4

0.29

MVP

0.32

MPC

0.15

ClinPred

0.031

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.092

gMVP

0.069

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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