rs147119902

chr14-58429365-T-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.202T>A(p.Ser68Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000889 in 1,575,674 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00076 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (11 hom.)
• Consequence: KIAA0586 NM_001329943.3 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.14

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=0.0069651008).
• BP6: Variant 14-58429365-T-A is Benign according to our data. Variant chr14-58429365-T-A is described in ClinVar as [Benign]. Clinvar id is 475443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000903 (1285/1423360) while in subpopulation EAS AF= 0.0112 (442/39346). AF 95% confidence interval is 0.0104. There are 11 homozygotes in gnomad4_exome. There are 757 alleles in male gnomad4_exome subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0586	NM_001329943.3	c.202T>A	p.Ser68Thr	missense_variant, splice_region_variant	2/31	ENST00000652326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0586	ENST00000652326.2	c.202T>A	p.Ser68Thr	missense_variant, splice_region_variant	2/31		NM_001329943.3	P4

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152196 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00185 AC: 461 AN: 248986 Hom.: 2 AF XY: 0.00199 AC XY: 269 AN XY: 135102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0106

Gnomad SAS exome AF: 0.00814

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000797

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000903 AC: 1285 AN: 1423360 Hom.: 11 Cov.: 26 AF XY: 0.00107 AC XY: 757 AN XY: 710658

Gnomad4 AFR exome AF: 0.0000612

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.0112

Gnomad4 SAS exome AF: 0.00795

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000557

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152314 Hom.: 1 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000472 Hom.: 0

Bravo AF: 0.000502

ExAC AF: 0.00194 AC: 234

Asia WGS AF: 0.0100 AC: 36 AN: 3474

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	KIAA0586: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2020	This variant is associated with the following publications: (PMID: 30993914) -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.55	T;T;T
MetaRNN	Benign	0.0070	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.67	N;.;N
REVEL	Benign	0.071
Sift	Benign	0.060	T;.;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.34	.;B;.
Vest4		0.29
MVP		0.32
MPC		0.15
ClinPred		0.031	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.092
gMVP		0.069

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs147119902; hg19: chr14-58896083;