14-58457939-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_001329943.3(KIAA0586):c.1543G>A(p.Ala515Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000609 in 1,602,212 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00062 ( 14 hom. )

Consequence

KIAA0586
NM_001329943.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.04

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Joubert syndrome 23
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
short-rib thoracic dysplasia 14 with polydactyly
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with Jeune asphyxiating thoracic dystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KIAA0586 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009586483).

BP6

Variant 14-58457939-G-A is Benign according to our data. Variant chr14-58457939-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 542188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00046 (70/152300) while in subpopulation SAS AF = 0.013 (63/4832). AF 95% confidence interval is 0.0105. There are 0 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 14 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 rank	MANE	Protein	UniProt
KIAA0586	NM_001329943.3 link	c.1543G>A	p.Ala515Thr	missense_variant	Exon 11 of 31	ENST00000652326.2	NP_001316872.1	A0A494C171

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIAA0586	ENST00000652326.2 link	c.1543G>A	p.Ala515Thr	missense_variant	Exon 11 of 31		NM_001329943.3	ENSP00000498929.1		A0A494C171

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0134

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00125

AC:

285

AN:

228896

AF XY:

0.00169

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000309

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000700

GnomAD4 exome

AF:

0.000625

AC:

906

AN:

1449912

Hom.:

Cov.:

AF XY:

0.000911

AC XY:

656

AN XY:

719830

show subpopulations

African (AFR)

AF:

0.0000600

AC:

AN:

33330

American (AMR)

AF:

0.0000232

AC:

AN:

43062

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25794

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39462

South Asian (SAS)

AF:

0.0103

AC:

866

AN:

83974

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52830

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1105686

Other (OTH)

AF:

0.000533

AC:

AN:

60022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000460

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41558

American (AMR)

AF:

0.000458

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.0130

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.00131

AC:

158

Asia WGS

AF:

0.00404

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KIAA0586: BP4, BS1, BS2 -

Feb 22, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.039

.;.;T;T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

0.0086

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

T;T;T;T;.;T

MetaRNN

Benign

0.0096

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

.;.;.;L;.;.

PhyloP100

3.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.3

N;.;.;.;N;D

REVEL

Benign

0.067

Sift

Benign

0.11

T;.;.;.;T;T

Sift4G

Benign

0.15

T;T;T;T;T;T

Polyphen

0.18

.;.;.;B;.;.

Vest4

0.23

MutPred

0.56

.;.;.;Gain of catalytic residue at Y503 (P = 0.0016);.;.;

MVP

0.37

MPC

0.027

ClinPred

0.038

GERP RS

4.2

Varity_R

0.087

gMVP

0.16

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over