rs372841738

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_001329943.3(KIAA0586):c.2944+4A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,433,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

KIAA0586
NM_001329943.3 splice_region, intron

Scores

Splicing: ADA: 0.07196

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 2.02

Publications

0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
short-rib thoracic dysplasia 14 with polydactyly
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-58477245-A-C is Pathogenic according to our data. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446. Variant chr14-58477245-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 475446.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIAA0586	NM_001329943.3 link	c.2944+4A>C		splice_region_variant, intron_variant	Intron 20 of 30	ENST00000652326.2	NP_001316872.1	A0A494C171

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIAA0586	ENST00000652326.2 link	c.2944+4A>C		splice_region_variant, intron_variant	Intron 20 of 30		NM_001329943.3	ENSP00000498929.1		A0A494C171

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000190

AC:

AN:

158096

AF XY:

0.0000240

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000475

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1280882

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

637966

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29138

American (AMR)

AF:

0.00

AC:

AN:

34724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24322

East Asian (EAS)

AF:

0.00

AC:

AN:

35842

South Asian (SAS)

AF:

0.00

AC:

AN:

76466

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5318

European-Non Finnish (NFE)

AF:

0.0000154

AC:

AN:

972450

Other (OTH)

AF:

0.00

AC:

AN:

54012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:1

Mar 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 22 of the KIAA0586 gene. It does not directly change the encoded amino acid sequence of the KIAA0586 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs372841738, gnomAD 0.003%). This variant has been observed in individual(s) with Joubert syndrome (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 475446). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided

Uncertain:1

Oct 20, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.9

(source)

DANN

Benign

0.62

PhyloP100

2.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.072

dbscSNV1_RF

Benign

0.42

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.42

Position offset: -4

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over