chr14-58482712-G-A

Variant names:

• chr14-58482712-G-A
• rs540255320
• NM_001329943.3:c.3144G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_001329943.3(KIAA0586):​c.3144G>A​(p.Pro1048Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000863 in 1,390,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001224722: Experimental studies have shown that this variant affects KIAA0586 function (PMID:2609613).".

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: KIAA0586 NM_001329943.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.43
• 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: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001224722: Experimental studies have shown that this variant affects KIAA0586 function (PMID: 2609613).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 14-58482712-G-A is Pathogenic according to our data. Variant chr14-58482712-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 217667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.3144G>A	p.Pro1048Pro	splice_region synonymous	Exon 21 of 31	NP_001316872.1	A0A494C171
	KIAA0586	NM_001244189.2		c.3303G>A	p.Pro1101Pro	splice_region synonymous	Exon 23 of 34	NP_001231118.1	Q9BVV6-3
	KIAA0586	NM_001329944.2		c.3144G>A	p.Pro1048Pro	splice_region synonymous	Exon 21 of 32	NP_001316873.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.3144G>A	p.Pro1048Pro	splice_region synonymous	Exon 21 of 31	ENSP00000498929.1	A0A494C171
	KIAA0586	ENST00000619416.4	TSL:1	c.3099G>A	p.Pro1033Pro	splice_region synonymous	Exon 22 of 32	ENSP00000478083.1	Q9BVV6-1
	KIAA0586	ENST00000423743.7	TSL:1	c.3012G>A	p.Pro1004Pro	splice_region synonymous	Exon 22 of 32	ENSP00000399427.3	Q9BVV6-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000244 AC: 5 AN: 205132 AF XY: 0.00000892

Gnomad AFR exome AF: 0.0000722

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000205

Gnomad FIN exome AF: 0.0000491

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000863 AC: 12 AN: 1390920 Hom.: 0 Cov.: 30 AF XY: 0.00000436 AC XY: 3 AN XY: 687852

African (AFR) AF: 0.0000330 AC: 1 AN: 30264

American (AMR) AF: 0.00 AC: 0 AN: 32954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23280

East Asian (EAS) AF: 0.0000533 AC: 2 AN: 37502

South Asian (SAS) AF: 0.0000261 AC: 2 AN: 76670

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51900

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5464

European-Non Finnish (NFE) AF: 0.00000372 AC: 4 AN: 1075904

Other (OTH) AF: 0.0000175 AC: 1 AN: 56982

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	18
DANN	Benign	0.35
PhyloP100		1.4
Mutation Taster		=37/63	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.79		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs540255320; hg19: chr14-58949430; COSMIC: COSV54174204;