14-58488812-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001329943.3(KIAA0586):c.3719T>C(p.Leu1240Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,613,894 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 18 hom., cov: 32)

Exomes 𝑓: 0.015 ( 206 hom. )

Consequence

KIAA0586
NM_001329943.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.451

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049393475).

BP6

Variant 14-58488812-T-C is Benign according to our data. Variant chr14-58488812-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475449.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 = 0.0117 (1789/152274) while in subpopulation SAS AF = 0.024 (116/4828). AF 95% confidence interval is 0.0205. There are 18 homozygotes in GnomAd4. There are 907 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIAA0586	NM_001329943.3 link	c.3719T>C	p.Leu1240Ser	missense_variant	Exon 24 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.3719T>C	p.Leu1240Ser	missense_variant	Exon 24 of 31		NM_001329943.3	ENSP00000498929.1		A0A494C171

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1789

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00304

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0171

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0163

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.0138

AC:

3442

AN:

249026

AF XY:

0.0151

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00669

Gnomad ASJ exome

AF:

0.00935

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.0173

Gnomad NFE exome

AF:

0.0168

Gnomad OTH exome

AF:

0.0187

GnomAD4 exome

AF:

0.0153

AC:

22362

AN:

1461620

Hom.:

206

Cov.:

AF XY:

0.0156

AC XY:

11349

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.00230

AC:

AN:

33478

American (AMR)

AF:

0.00713

AC:

319

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

296

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.0238

AC:

2056

AN:

86254

European-Finnish (FIN)

AF:

0.0175

AC:

937

AN:

53402

Middle Eastern (MID)

AF:

0.0380

AC:

219

AN:

5768

European-Non Finnish (NFE)

AF:

0.0157

AC:

17501

AN:

1111800

Other (OTH)

AF:

0.0158

AC:

956

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1259

2518

3777

5036

6295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

656

1312

1968

2624

3280

<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:

0.0117

AC:

1789

AN:

152274

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

907

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00303

AC:

126

AN:

41556

American (AMR)

AF:

0.0114

AC:

175

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0240

AC:

116

AN:

4828

European-Finnish (FIN)

AF:

0.0171

AC:

182

AN:

10614

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0163

AC:

1110

AN:

68014

Other (OTH)

AF:

0.0147

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

174

262

349

436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0142

Hom.:

Bravo

AF:

0.0110

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00215

AC:

ESP6500EA

AF:

0.0128

AC:

105

ExAC

AF:

0.0144

AC:

1735

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0164

EpiControl

AF:

0.0175

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

Oct 29, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.028

.;.;T;T;.;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.52

T;T;T;T;.;T

MetaRNN

Benign

0.0049

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

.;.;.;L;.;.

PhyloP100

0.45

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.8

N;.;.;.;N;N

REVEL

Benign

0.024

Sift

Benign

0.093

T;.;.;.;T;T

Sift4G

Benign

0.22

T;T;T;T;T;T

Polyphen

0.019

.;.;.;B;.;.

Vest4

0.14

MPC

0.024

ClinPred

0.0031

GERP RS

1.5

Varity_R

0.051

gMVP

0.10

Mutation Taster

=98/2

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

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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