rs568910724

chr14-58457939-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001329943.3(KIAA0586):c.1543G>A(p.Ala515Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000609 in 1,602,212 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (14 hom.)
• Consequence: KIAA0586 NM_001329943.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.04

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009586483).
• BP6: Variant 14-58457939-G-A is Benign according to our data. Variant chr14-58457939-G-A is described in ClinVar as [Benign]. Clinvar id is 542188.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00046 (70/152300) while in subpopulation SAS AF= 0.013 (63/4832). AF 95% confidence interval is 0.0105. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. 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.1543G>A	p.Ala515Thr	missense_variant	11/31	ENST00000652326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0586	ENST00000652326.2	c.1543G>A	p.Ala515Thr	missense_variant	11/31		NM_001329943.3	P4

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0134

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00125 AC: 285 AN: 228896 Hom.: 2 AF XY: 0.00169 AC XY: 208 AN XY: 123418

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000309

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000700

GnomAD4 exome AF: 0.000625 AC: 906 AN: 1449912 Hom.: 14 Cov.: 31 AF XY: 0.000911 AC XY: 656 AN XY: 719830

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.0000232

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0103

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.000533

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0130

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.00131 AC: 158

Asia WGS AF: 0.00404 AC: 16 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	19
Dann	Uncertain	0.97
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0086
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;T;T;T;.;T
MetaRNN	Benign	0.0096	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.97	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N;.;.;.;N;D
REVEL	Benign	0.067
Sift	Benign	0.11	T;.;.;.;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T
Polyphen		0.18	.;.;.;B;.;.
Vest4		0.23
MutPred		0.56		.;.;.;Gain of catalytic residue at Y503 (P = 0.0016);.;.;
MVP		0.37
MPC		0.027
ClinPred		0.038	T
GERP RS		4.2
Varity_R		0.087
gMVP		0.16

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: rs568910724; hg19: chr14-58924657;