rs77860620

chr14-58482672-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 14/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.289

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]

ACMG classification

Verdict is Benign. Variant got -20 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 id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0586	NM_001329943.3	c.3104G>A	p.Gly1035Asp	missense_variant	21/31	ENST00000652326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0586	ENST00000652326.2	c.3104G>A	p.Gly1035Asp	missense_variant	21/31		NM_001329943.3	P4

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 97 AN: 152142 Hom.: 2 Cov.: 31

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

GnomAD3 exomes AF: 0.00128 AC: 292 AN: 228560 Hom.: 7 AF XY: 0.00116 AC XY: 144 AN XY: 124036

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 SAS exome AF: 0.000655

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.: 19 Cov.: 32 AF XY: 0.000698 AC XY: 498 AN XY: 713418

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0201

Gnomad4 SAS exome AF: 0.000884

Gnomad4 FIN exome AF: 0.000830

Gnomad4 NFE exome AF: 0.0000390

Gnomad4 OTH exome AF: 0.000574

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152260 Hom.: 2 Cov.: 31 AF XY: 0.000739 AC XY: 55 AN XY: 74456

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0131

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00104 Hom.: 4

Bravo AF: 0.000518

ExAC AF: 0.00148 AC: 179

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

KIAA0586: BP4, BS1, BS2 -

Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

KIAA0586-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2019

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	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.50
Dann	Benign	0.14
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.79	T;T;T;T;.;T
MetaRNN	Benign	0.0039	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
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	T
GERP RS		1.5
Varity_R		0.043
gMVP		0.065

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

Other links and lift over

dbSNP: rs77860620; hg19: chr14-58949390; COSMIC: COSV54171338;