rs534542684

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS2_Supporting

The NM_001329943.3(KIAA0586):c.392delG(p.Arg131LysfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00383 in 1,568,644 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0034 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 14 hom. )

Consequence

KIAA0586
NM_001329943.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:43O:1

Conservation

PhyloP100: 4.54

Publications

31 publications found

Variant links:

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

KIAA0586 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 14-58432438-AG-A is Pathogenic according to our data. Variant chr14-58432438-AG-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 204593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIAA0586	NM_001329943.3	MANE Select	c.392delG	p.Arg131LysfsTer4	frameshift	Exon 4 of 31	NP_001316872.1	A0A494C171
KIAA0586	NM_001244189.2		c.428delG	p.Arg143LysfsTer4	frameshift	Exon 5 of 34	NP_001231118.1	Q9BVV6-3
KIAA0586	NM_001329944.2		c.392delG	p.Arg131LysfsTer4	frameshift	Exon 4 of 32	NP_001316873.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIAA0586	ENST00000652326.2	MANE Select	c.392delG	p.Arg131LysfsTer4	frameshift	Exon 4 of 31	ENSP00000498929.1	A0A494C171
KIAA0586	ENST00000619416.4	TSL:1	c.347delG	p.Arg116LysfsTer4	frameshift	Exon 5 of 32	ENSP00000478083.1	Q9BVV6-1
KIAA0586	ENST00000423743.7	TSL:1	c.137delG	p.Arg46LysfsTer4	frameshift	Exon 4 of 32	ENSP00000399427.3	Q9BVV6-4

Frequencies

GnomAD3 genomes

AF:

0.00342

AC:

521

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00556

Gnomad ASJ

AF:

0.00952

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00500

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00305

AC:

664

AN:

217674

AF XY:

0.00308

show subpopulations

Gnomad AFR exome

AF:

0.000956

Gnomad AMR exome

AF:

0.00237

Gnomad ASJ exome

AF:

0.00816

Gnomad EAS exome

AF:

0.0000640

Gnomad FIN exome

AF:

0.000711

Gnomad NFE exome

AF:

0.00462

Gnomad OTH exome

AF:

0.00233

GnomAD4 exome

AF:

0.00388

AC:

5494

AN:

1416304

Hom.:

Cov.:

AF XY:

0.00386

AC XY:

2721

AN XY:

704672

show subpopulations

African (AFR)

AF:

0.000670

AC:

AN:

31354

American (AMR)

AF:

0.00313

AC:

116

AN:

37116

Ashkenazi Jewish (ASJ)

AF:

0.00937

AC:

235

AN:

25078

East Asian (EAS)

AF:

0.0000524

AC:

AN:

38138

South Asian (SAS)

AF:

0.000584

AC:

AN:

78772

European-Finnish (FIN)

AF:

0.000927

AC:

AN:

52882

Middle Eastern (MID)

AF:

0.00282

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.00440

AC:

4789

AN:

1088700

Other (OTH)

AF:

0.00375

AC:

220

AN:

58598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

209

418

627

836

1045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

170

340

510

680

850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00342

AC:

521

AN:

152340

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

260

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

41574

American (AMR)

AF:

0.00555

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00952

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00498

AC:

339

AN:

68034

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00372

Hom.:

Bravo

AF:

0.00396

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Joubert syndrome 23 (16)

not provided (14)

Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly (4)

Joubert syndrome (2)

Short-rib thoracic dysplasia 14 with polydactyly (2)

Inborn genetic diseases (1)

Intellectual disability;C4551714:Rod-cone dystrophy;C5231391:Congenital cerebellar hypoplasia (1)

Joubert syndrome and related disorders (1)

KIAA0586- Related disorders (1)

KIAA0586-related disorder (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.5

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over