chr14-58448363-C-T

Variant names:

• chr14-58448363-C-T
• rs780520735
• NM_001329943.3:c.831C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PP5_Moderate BP4 BP7

The NM_001329943.3(KIAA0586):​c.831C>T​(p.Leu277Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000968 in 1,445,542 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L277L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: KIAA0586 NM_001329943.3 synonymous
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.383
• Publications: 1 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• short-rib thoracic dysplasia 14 with polydactyly

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-58448363-C-T is Pathogenic according to our data. Variant chr14-58448363-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 475455.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65). . Strength limited to SUPPORTING due to the PP5.
• BP7: Synonymous conserved (PhyloP=0.383 with no splicing effect.

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.831C>T	p.Leu277Leu	synonymous	Exon 7 of 31	NP_001316872.1	A0A494C171
	KIAA0586	NM_001244189.2		c.990C>T	p.Leu330Leu	synonymous	Exon 9 of 34	NP_001231118.1	Q9BVV6-3
	KIAA0586	NM_001329944.2		c.831C>T	p.Leu277Leu	synonymous	Exon 7 of 32	NP_001316873.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.831C>T	p.Leu277Leu	synonymous	Exon 7 of 31	ENSP00000498929.1	A0A494C171
	KIAA0586	ENST00000619416.4	TSL:1	c.786C>T	p.Leu262Leu	synonymous	Exon 8 of 32	ENSP00000478083.1	Q9BVV6-1
	KIAA0586	ENST00000423743.7	TSL:1	c.699C>T	p.Leu233Leu	synonymous	Exon 8 of 32	ENSP00000399427.3	Q9BVV6-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000285 AC: 7 AN: 245872 AF XY: 0.0000450

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: 0.0000625

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000968 AC: 14 AN: 1445542 Hom.: 0 Cov.: 27 AF XY: 0.0000125 AC XY: 9 AN XY: 719836

African (AFR) AF: 0.00 AC: 0 AN: 33034

American (AMR) AF: 0.00 AC: 0 AN: 43722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25944

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.00 AC: 0 AN: 84976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.0000127 AC: 14 AN: 1099548

Other (OTH) AF: 0.00 AC: 0 AN: 59788

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
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	-0.65
CADD	Benign	8.3
DANN	Benign	0.69
PhyloP100		0.38
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs780520735; hg19: chr14-58915081;