14-58450673-A-T

Variant names:

• chr14-58450673-A-T
• NM_001329943.3:c.1056A>T
• KIAA0586 p.Ser352Ser

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001329943.3(KIAA0586):​c.1056A>T​(p.Ser352Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S352S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIAA0586 NM_001329943.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.328
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1056A>T	p.Ser352Ser	synonymous	Exon 8 of 31	NP_001316872.1	A0A494C171
	KIAA0586	NM_001244189.2		c.1215A>T	p.Ser405Ser	synonymous	Exon 10 of 34	NP_001231118.1	Q9BVV6-3
	KIAA0586	NM_001329944.2		c.1056A>T	p.Ser352Ser	synonymous	Exon 8 of 32	NP_001316873.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.1056A>T	p.Ser352Ser	synonymous	Exon 8 of 31	ENSP00000498929.1	A0A494C171
	KIAA0586	ENST00000619416.4	TSL:1	c.1011A>T	p.Ser337Ser	synonymous	Exon 9 of 32	ENSP00000478083.1	Q9BVV6-1
	KIAA0586	ENST00000423743.7	TSL:1	c.924A>T	p.Ser308Ser	synonymous	Exon 9 of 32	ENSP00000399427.3	Q9BVV6-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.64
PhyloP100		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: 3

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr14-58917391;