rs796052129

Positions:

• chr14-58457934-A-G
• chr14-58457934-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001329943.3(KIAA0586):​c.1538A>G​(p.Asp513Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KIAA0586 NM_001329943.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.34

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39131826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIAA0586	NM_001329943.3	c.1538A>G	p.Asp513Gly	missense_variant	11/31	ENST00000652326.2	NP_001316872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIAA0586	ENST00000652326.2	c.1538A>G	p.Asp513Gly	missense_variant	11/31		NM_001329943.3	ENSP00000498929	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451148 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

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. 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. This variant has not been reported in the literature in individuals affected with KIAA0586-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 566 of the KIAA0586 protein (p.Asp566Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;.;T;D;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D;D;D;.;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.39	T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.3	.;.;.;M;.;.
MutationTaster	Benign	0.93	D;D;D;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.6	D;.;.;.;D;D
REVEL	Benign	0.27
Sift	Benign	0.15	T;.;.;.;T;D
Sift4G	Benign	0.14	T;T;T;T;T;T
Polyphen		0.97	.;.;.;D;.;.
Vest4		0.83
MutPred		0.54		.;.;.;Gain of catalytic residue at G499 (P = 2e-04);.;.;
MVP		0.70
MPC		0.17
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.30
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs796052129; hg19: chr14-58924652;