rs748594194

Variant names:

• chr14-58482492-ATTT-A
• rs748594194
• NM_001329943.3:c.2945-11_2945-9delTTT

Your query was ambiguous. Multiple possible variants found:

• chr14-58482492-ATTT-A
• chr14-58482492-ATTT-AT
• chr14-58482492-ATTT-ATT
• chr14-58482492-ATTT-ATTTT
• chr14-58482492-ATTT-ATTTTT
• chr14-58482492-ATTT-ATTTTTT
• chr14-58482492-ATTT-ATTTTTTT

Variant summary

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

The NM_001329943.3(KIAA0586):​c.2945-11_2945-9delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000607 in 988,540 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000061 (0 hom.)
• Consequence: KIAA0586 NM_001329943.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.360
• 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.2945-11_2945-9delTTT		intron	N/A	NP_001316872.1
	KIAA0586	NM_001244189.2		c.3104-11_3104-9delTTT		intron	N/A	NP_001231118.1
	KIAA0586	NM_001329944.2		c.2945-11_2945-9delTTT		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.2945-20_2945-18delTTT		intron	N/A	ENSP00000498929.1
	KIAA0586	ENST00000619416.4	TSL:1	c.2900-20_2900-18delTTT		intron	N/A	ENSP00000478083.1
	KIAA0586	ENST00000423743.7	TSL:1	c.2813-20_2813-18delTTT		intron	N/A	ENSP00000399427.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000166 AC: 1 AN: 60246 AF XY: 0.00

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: 0.0000330

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000607 AC: 6 AN: 988540 Hom.: 0 AF XY: 0.00000618 AC XY: 3 AN XY: 485148

⚠️ 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: 20736

American (AMR) AF: 0.00 AC: 0 AN: 20024

Ashkenazi Jewish (ASJ) AF: 0.0000631 AC: 1 AN: 15858

East Asian (EAS) AF: 0.00 AC: 0 AN: 27524

South Asian (SAS) AF: 0.0000204 AC: 1 AN: 49074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38070

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

European-Non Finnish (NFE) AF: 0.00000517 AC: 4 AN: 773280

Other (OTH) AF: 0.00 AC: 0 AN: 40432

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000957807), 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		0.36
BranchPoint Hunter		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs748594194; hg19: chr14-58949210;