rs199537542

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001329943.3(KIAA0586):c.3003C>A(p.Asn1001Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,599,838 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

KIAA0586
NM_001329943.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.331

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26135385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0586	NM_001329943.3 linkuse as main transcript	c.3003C>A	p.Asn1001Lys	missense_variant	21/31	ENST00000652326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0586	ENST00000652326.2 linkuse as main transcript	c.3003C>A	p.Asn1001Lys	missense_variant	21/31		NM_001329943.3	P4

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

151816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000162

AC:

AN:

241288

Hom.:

AF XY:

0.000160

AC XY:

AN XY:

131038

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000154

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000257

AC:

372

AN:

1448022

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

169

AN XY:

719998

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.000161

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000315

Gnomad4 OTH exome

AF:

0.000268

GnomAD4 genome

AF:

0.000184

AC:

AN:

151816

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74114

show subpopulations

Gnomad4 AFR

AF:

0.0000726

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000254

Hom.:

Bravo

AF:

0.000185

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000486

AC:

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1054 of the KIAA0586 protein (p.Asn1054Lys). This variant is present in population databases (rs199537542, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with KIAA0586-related conditions. ClinVar contains an entry for this variant (Variation ID: 542185). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KIAA0586 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 21, 2021	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	KIAA0586: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 21, 2020

DNA sequence analysis of the KIAA0586 gene demonstrated a sequence change, c.3162C>A, in exon 23 that results in an amino acid change, p.Asn1054Lys. This sequence change does not appear to have been previously described in patients with KIAA0586-related disorders and has been described in the gnomAD database with a low population frequency of 0.030% in non-Finnish European subpopulation (dbSNP rs199537542). The p.Asn1054Lys change affects a moderately conserved amino acid residue located in a domain of the KIAA0586 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asn1054Lys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asn1054Lys change remains unknown at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.38

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.89

D;D;D;D;.;D

M_CAP

Benign

0.039

MetaRNN

Benign

0.26

T;T;T;T;T;T

MetaSVM

Benign

-0.63

MutationTaster

Benign

0.58

N;N;N;N

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-4.2

D;.;.;.;D;D

REVEL

Benign

0.15

Sift

Uncertain

0.0050

D;.;.;.;D;D

Sift4G

Uncertain

0.023

D;D;D;D;D;D

Polyphen

0.93

.;.;.;P;.;.

Vest4

0.56

MutPred

0.47

.;.;.;Gain of catalytic residue at N986 (P = 0);.;.;

MVP

0.38

MPC

0.059

ClinPred

0.33

GERP RS

-0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.20

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

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