14-58482492-ATTT-ATTTTTTT

Variant names:

• chr14-58482492-A-ATTTT
• rs748594194
• NM_001329943.3:c.2945-12_2945-9dupTTTT

Variant summary

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

The NM_001329943.3(KIAA0586):​c.2945-12_2945-9dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000101 in 988,724 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: KIAA0586 NM_001329943.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280
• 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), Ambry Genetics, G2P
• short-rib thoracic dysplasia 14 with polydactyly

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	NM_001329943.3	MANE Select	c.2945-12_2945-9dupTTTT		splice_region intron	N/A	NP_001316872.1
	KIAA0586	NM_001244189.2		c.3104-12_3104-9dupTTTT		splice_region intron	N/A	NP_001231118.1
	KIAA0586	NM_001329944.2		c.2945-12_2945-9dupTTTT		splice_region intron	N/A	NP_001316873.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.2945-21_2945-20insTTTT		intron	N/A	ENSP00000498929.1
	KIAA0586	ENST00000619416.4	TSL:1	c.2900-21_2900-20insTTTT		intron	N/A	ENSP00000478083.1
	KIAA0586	ENST00000423743.7	TSL:1	c.2813-21_2813-20insTTTT		intron	N/A	ENSP00000399427.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000101 AC: 1 AN: 988724 Hom.: 0 Cov.: 0 AF XY: 0.00000206 AC XY: 1 AN XY: 485226

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20740

American (AMR) AF: 0.00 AC: 0 AN: 20026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15860

East Asian (EAS) AF: 0.00 AC: 0 AN: 27526

South Asian (SAS) AF: 0.00 AC: 0 AN: 49086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3542

European-Non Finnish (NFE) AF: 0.00000129 AC: 1 AN: 773424

Other (OTH) AF: 0.00 AC: 0 AN: 40442

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.028
BranchPoint Hunter		4.0

Splicing

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

Other links and lift over

dbSNP: rs748594194; hg19: chr14-58949210;