14-58457934-A-T

Variant names:

• chr14-58457934-A-T
• rs796052129
• NM_001329943.3:c.1538A>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001329943.3(KIAA0586):​c.1538A>T​(p.Asp513Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,451,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D513G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KIAA0586 NM_001329943.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.34
• Publications: 4 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766
• PP5: Variant 14-58457934-A-T is Pathogenic according to our data. Variant chr14-58457934-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 204597.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1538A>T	p.Asp513Val	missense	Exon 11 of 31	NP_001316872.1	A0A494C171
	KIAA0586	NM_001244189.2		c.1697A>T	p.Asp566Val	missense	Exon 13 of 34	NP_001231118.1	Q9BVV6-3
	KIAA0586	NM_001329944.2		c.1538A>T	p.Asp513Val	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.1538A>T	p.Asp513Val	missense	Exon 11 of 31	ENSP00000498929.1	A0A494C171
	KIAA0586	ENST00000619416.4	TSL:1	c.1493A>T	p.Asp498Val	missense	Exon 12 of 32	ENSP00000478083.1	Q9BVV6-1
	KIAA0586	ENST00000423743.7	TSL:1	c.1406A>T	p.Asp469Val	missense	Exon 12 of 32	ENSP00000399427.3	Q9BVV6-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000434 AC: 1 AN: 230642 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1451148 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720602

African (AFR) AF: 0.00 AC: 0 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 43254

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25834

East Asian (EAS) AF: 0.00 AC: 0 AN: 39466

South Asian (SAS) AF: 0.00 AC: 0 AN: 84184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52888

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106366

Other (OTH) AF: 0.00 AC: 0 AN: 60052

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Joubert syndrome 23 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.52		Gain of catalytic residue at D498 (P = 0)
MVP		0.80
MPC		0.17
ClinPred		0.94	D
GERP RS		6.0
Varity_R		0.39
gMVP		0.43
Mutation Taster		=14/86	disease causing (ClinVar)

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: rs796052129; hg19: chr14-58924652;