Genetic Variant KIAA0586:c.-45G>A (chr14-58427631-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PVS1_Supporting

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.551

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 links:

TIMM9 (HGNC:11819): (translocase of inner mitochondrial membrane 9) TIMM9 belongs to a family of evolutionarily conserved proteins that are organized in heterooligomeric complexes in the mitochondrial intermembrane space. These proteins mediate the import and insertion of hydrophobic membrane proteins into the mitochondrial inner membrane.[supplied by OMIM, Apr 2004]

TIMM9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 13 codons. Genomic position: 58428265. Lost 0.007 part of the original CDS.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244189.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIAA0586	NM_001244189.2	c.3G>A	p.Met1?	start_lost	Exon 1 of 34	NP_001231118.1	Q9BVV6-3
KIAA0586	NM_001244190.2	c.-45G>A		5_prime_UTR	Exon 1 of 32	NP_001231119.1	Q9BVV6-1
KIAA0586	NM_001244192.2	c.-63G>A		5_prime_UTR	Exon 1 of 32	NP_001231121.1	Q9BVV6-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIAA0586	ENST00000619416.4	TSL:1	c.-45G>A		5_prime_UTR	Exon 1 of 32	ENSP00000478083.1	Q9BVV6-1
KIAA0586	ENST00000423743.7	TSL:1	c.-63G>A		5_prime_UTR	Exon 1 of 32	ENSP00000399427.3	Q9BVV6-4
KIAA0586	ENST00000354386.10	TSL:2	c.3G>A	p.Met1?	start_lost	Exon 1 of 34	ENSP00000346359.6	Q9BVV6-3

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000224

AC:

AN:

129466

AF XY:

0.000169

show subpopulations

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 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.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

682586

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31594

American (AMR)

AF:

0.000980

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35732

South Asian (SAS)

AF:

0.00

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.0000881

AC:

AN:

1078874

Other (OTH)

AF:

0.000190

AC:

AN:

57900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.000184

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00124

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68046

Other (OTH)

AF:

0.000958

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000310

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.51

CADD

Benign

5.7

(source)

DANN

Benign

0.97

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.094

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.017

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.97

PhyloP100

0.55

PROVEAN

Benign

-0.17

REVEL

Benign

0.081

Sift

Pathogenic

0.0

Vest4

0.18

MutPred

0.75

Loss of disorder (P = 0.0444)

MVP

0.41

ClinPred

0.13

GERP RS

1.9

PromoterAI

-0.044

Neutral

(source)

gMVP

0.040

Mutation Taster

=156/44

polymorphism

(source)

Splicing

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