rs77860620

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.3104G>A(p.Gly1035Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000678 in 1,588,580 control chromosomes in the GnomAD database, including 21 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 Benign (★★).

Frequency

Genomes: 𝑓 0.00064 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00068 ( 19 hom. )

Consequence

KIAA0586
NM_001329943.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.289

Publications

5 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=0.0039307475).

BP6

Variant 14-58482672-G-A is Benign according to our data. Variant chr14-58482672-G-A is described in ClinVar as Benign. ClinVar VariationId is 475447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000637 (97/152260) while in subpopulation EAS AF = 0.0131 (68/5180). AF 95% confidence interval is 0.0106. There are 2 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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.3104G>A	p.Gly1035Asp	missense_variant	Exon 21 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.3104G>A	p.Gly1035Asp	missense_variant	Exon 21 of 31		NM_001329943.3	ENSP00000498929.1		A0A494C171

Frequencies

GnomAD3 genomes

AF:

0.000638

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0131

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00128

AC:

292

AN:

228560

AF XY:

0.00116

show subpopulations

Gnomad AFR exome

AF:

0.0000672

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0152

Gnomad FIN exome

AF:

0.000753

Gnomad NFE exome

AF:

0.0000562

Gnomad OTH exome

AF:

0.000184

GnomAD4 exome

AF:

0.000682

AC:

980

AN:

1436320

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

498

AN XY:

713418

show subpopulations

African (AFR)

AF:

0.0000311

AC:

AN:

32174

American (AMR)

AF:

0.00

AC:

AN:

39442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25112

East Asian (EAS)

AF:

0.0201

AC:

784

AN:

38980

South Asian (SAS)

AF:

0.000884

AC:

AN:

81450

European-Finnish (FIN)

AF:

0.000830

AC:

AN:

53042

Middle Eastern (MID)

AF:

0.000354

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.0000390

AC:

AN:

1101204

Other (OTH)

AF:

0.000574

AC:

AN:

59268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

109

164

218

273

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:

0.000637

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41556

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0131

AC:

AN:

5180

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68016

Other (OTH)

AF:

0.000473

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

Genome Hom

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:

0.000890

Hom.:

Bravo

AF:

0.000518

ExAC

AF:

0.00148

AC:

179

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KIAA0586: BP4, BS1, BS2 -

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

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KIAA0586-related disorder

Benign:1

Mar 25, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.50

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.014

.;.;T;T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.79

T;T;T;T;.;T

MetaRNN

Benign

0.0039

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;.;.;L;.;.

PhyloP100

-0.29

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.97

N;.;.;.;N;N

REVEL

Benign

0.044

Sift

Benign

0.35

T;.;.;.;T;T

Sift4G

Benign

0.30

T;T;T;T;T;T

Polyphen

0.0

.;.;.;B;.;.

Vest4

0.094

MVP

0.21

MPC

0.021

ClinPred

0.0080

GERP RS

1.5

Varity_R

0.043

gMVP

0.065

Mutation Taster

=100/0

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