rs45568037

Positions:

• chr14-58547845-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_001244189.2(KIAA0586):​c.4804G>A​(p.Val1602Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,613,662 control chromosomes in the GnomAD database, including 204 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (25 hom., cov: 32)
  • Exomes 𝑓: 0.013 (179 hom.)
• Consequence: KIAA0586 NM_001244189.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.386

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026349127).
• BP6: Variant 14-58547845-G-A is Benign according to our data. Variant chr14-58547845-G-A is described in ClinVar as [Benign]. Clinvar id is 475454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0121 (1843/152230) while in subpopulation NFE AF= 0.02 (1360/68006). AF 95% confidence interval is 0.0191. There are 25 homozygotes in gnomad4. There are 864 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIAA0586	NM_001329943.3	c.4560G>A	p.Pro1520Pro	synonymous_variant	31/31	ENST00000652326.2	NP_001316872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIAA0586	ENST00000652326.2	c.4560G>A	p.Pro1520Pro	synonymous_variant	31/31		NM_001329943.3	ENSP00000498929.1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1844 AN: 152112 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0200

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.0108 AC: 2674 AN: 248598 Hom.: 27 AF XY: 0.0108 AC XY: 1460 AN XY: 134848

Gnomad AFR exome AF: 0.00200

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00310

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0130 AC: 19003 AN: 1461432 Hom.: 179 Cov.: 32 AF XY: 0.0131 AC XY: 9530 AN XY: 727010

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.00311

Gnomad4 ASJ exome AF: 0.0238

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00326

Gnomad4 FIN exome AF: 0.0180

Gnomad4 NFE exome AF: 0.0146

Gnomad4 OTH exome AF: 0.0118

GnomAD4 genome AF: 0.0121 AC: 1843 AN: 152230 Hom.: 25 Cov.: 32 AF XY: 0.0116 AC XY: 864 AN XY: 74446

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.00635

Gnomad4 ASJ AF: 0.0253

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0169

Gnomad4 NFE AF: 0.0200

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.0177 Hom.: 25

Bravo AF: 0.00936

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00217 AC: 9

ESP6500EA AF: 0.0141 AC: 119

ExAC AF: 0.0112 AC: 1351

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KIAA0586: BP4, BS1, BS2 -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.6
DANN	Uncertain	0.98
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.061
Sift	Pathogenic	0.0	D
Vest4		0.15
MPC		0.018
ClinPred		0.0053	T
GERP RS		0.68
gMVP		0.0089

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: rs45568037; hg19: chr14-59014563; COSMIC: COSV54181863;