14-58427631-G-A

Position:

• chr14-58427631-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001244189.2(KIAA0586):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,535,590 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: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: KIAA0586 NM_001244189.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.551

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIAA0586	NM_001244189.2	c.3G>A	p.Met1?	start_lost	1/34		NP_001231118.1
KIAA0586	NM_001244190.2	c.-45G>A		5_prime_UTR_variant	1/32		NP_001231119.1
KIAA0586	NM_001244192.2	c.-63G>A		5_prime_UTR_variant	1/32		NP_001231121.1
KIAA0586	NM_001244191.2	c.-63G>A		5_prime_UTR_variant	1/31		NP_001231120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIAA0586	ENST00000619416	c.-45G>A		5_prime_UTR_variant	1/32	1		ENSP00000478083.1
KIAA0586	ENST00000423743	c.-63G>A		5_prime_UTR_variant	1/32	1		ENSP00000399427.3
KIAA0586	ENST00000354386.10	c.3G>A	p.Met1?	start_lost	1/34	2		ENSP00000346359.6
KIAA0586	ENST00000619722	c.-63G>A		5_prime_UTR_variant	1/31	2		ENSP00000481936.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000224 AC: 29 AN: 129466 Hom.: 0 AF XY: 0.000169 AC XY: 12 AN XY: 70840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000944

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000821

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000103 AC: 142 AN: 1383376 Hom.: 0 Cov.: 30 AF XY: 0.0000894 AC XY: 61 AN XY: 682586

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.000980

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: 0.0000881

Gnomad4 OTH exome AF: 0.000190

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000958

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000310

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2024

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

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

Jan 01, 2024

This sequence change affects the initiator methionine of the KIAA0586 mRNA. The next in-frame methionine is located at codon 13. This variant is present in population databases (rs753810786, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with KIAA0586-related conditions. ClinVar contains an entry for this variant (Variation ID: 1375585). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.7
DANN	Benign	0.97
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.094	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.081
Sift	Pathogenic	0.0	D
Vest4		0.18
MutPred		0.75		Loss of disorder (P = 0.0444);
MVP		0.41
ClinPred		0.13	T
GERP RS		1.9
gMVP		0.040

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs753810786; hg19: chr14-58894349;