rs61735931

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001329943.3(KIAA0586):c.422T>C(p.Met141Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00673 in 1,567,602 control chromosomes in the GnomAD database, including 54 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M141V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0052 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0069 ( 51 hom. )

Consequence

KIAA0586
NM_001329943.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.497

Publications

9 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061211884).

BP6

Variant 14-58442717-T-C is Benign according to our data. Variant chr14-58442717-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIAA0586	NM_001329943.3 link	c.422T>C	p.Met141Thr	missense_variant	Exon 5 of 31	ENST00000652326.2	NP_001316872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIAA0586	ENST00000652326.2 link	c.422T>C	p.Met141Thr	missense_variant	Exon 5 of 31		NM_001329943.3	ENSP00000498929.1

Frequencies

GnomAD3 genomes

AF:

0.00519

AC:

790

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00481

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00810

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00509

AC:

939

AN:

184644

AF XY:

0.00490

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00289

Gnomad ASJ exome

AF:

0.00956

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00519

Gnomad NFE exome

AF:

0.00765

Gnomad OTH exome

AF:

0.00750

GnomAD4 exome

AF:

0.00690

AC:

9766

AN:

1415288

Hom.:

Cov.:

AF XY:

0.00682

AC XY:

4774

AN XY:

699890

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

32424

American (AMR)

AF:

0.00349

AC:

130

AN:

37202

Ashkenazi Jewish (ASJ)

AF:

0.0108

AC:

272

AN:

25290

East Asian (EAS)

AF:

0.00

AC:

AN:

37930

South Asian (SAS)

AF:

0.00137

AC:

110

AN:

80386

European-Finnish (FIN)

AF:

0.00617

AC:

314

AN:

50884

Middle Eastern (MID)

AF:

0.00210

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00786

AC:

8541

AN:

1086730

Other (OTH)

AF:

0.00603

AC:

354

AN:

58736

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

417

835

1252

1670

2087

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

326

652

978

1304

1630

<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:

0.00519

AC:

790

AN:

152314

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

341

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

41586

American (AMR)

AF:

0.00425

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00481

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00810

AC:

551

AN:

68032

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

126

168

210

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:

0.00701

Hom.:

Bravo

AF:

0.00484

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00769

AC:

ExAC

AF:

0.00424

AC:

506

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 21, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KIAA0586: BP4, BS2 -

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

0.14

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.023

.;.;T;T;.;T;T;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.65

T;T;T;T;.;T;T;T

MetaRNN

Benign

0.0061

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;.;.;L;.;.;.;.

PhyloP100

0.50

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.5

N;.;.;.;N;N;N;N

REVEL

Benign

0.035

Sift

Benign

0.14

T;.;.;.;T;T;T;T

Sift4G

Benign

0.18

T;T;T;T;T;T;T;T

Polyphen

0.0030

.;.;.;B;.;.;.;.

Vest4

0.32

MVP

0.42

MPC

0.036

ClinPred

0.0049

GERP RS

1.3

Varity_R

0.090

gMVP

0.035

Mutation Taster

=95/5

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