rs568910724

Variant names:

• chr14-58457939-G-A
• rs568910724
• NM_001329943.3:c.1543G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BS1 BS2_Supporting

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.04
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Joubert syndrome 23

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• short-rib thoracic dysplasia 14 with polydactyly

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with Jeune asphyxiating thoracic dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 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/Likely_benign. ClinVar VariationId is 542188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329943.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	NM_001329943.3	MANE Select	c.1543G>A	p.Ala515Thr	missense	Exon 11 of 31	NP_001316872.1	A0A494C171
	KIAA0586	NM_001244189.2		c.1702G>A	p.Ala568Thr	missense	Exon 13 of 34	NP_001231118.1	Q9BVV6-3
	KIAA0586	NM_001329944.2		c.1543G>A	p.Ala515Thr	missense	Exon 11 of 32	NP_001316873.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.1543G>A	p.Ala515Thr	missense	Exon 11 of 31	ENSP00000498929.1	A0A494C171
	KIAA0586	ENST00000619416.4	TSL:1	c.1498G>A	p.Ala500Thr	missense	Exon 12 of 32	ENSP00000478083.1	Q9BVV6-1
	KIAA0586	ENST00000423743.7	TSL:1	c.1411G>A	p.Ala471Thr	missense	Exon 12 of 32	ENSP00000399427.3	Q9BVV6-4

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

GnomAD2 exomes AF: 0.00125 AC: 285 AN: 228896 AF XY: 0.00169

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 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

African (AFR) AF: 0.0000600 AC: 2 AN: 33330

American (AMR) AF: 0.0000232 AC: 1 AN: 43062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39462

South Asian (SAS) AF: 0.0103 AC: 866 AN: 83974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52830

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5752

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105686

Other (OTH) AF: 0.000533 AC: 32 AN: 60022

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

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.000458 AC: 7 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0130 AC: 63 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2112

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0086
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.067
Sift	Benign	0.11	T
Sift4G	Benign	0.15	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
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs568910724; hg19: chr14-58924657;