chr14-58482492-ATT-A

Variant names:

• chr14-58482492-ATT-A
• rs748594194
• NM_001329943.3:c.2945-10_2945-9delTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001329943.3(KIAA0586):​c.2945-10_2945-9delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000372 in 982,266 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIAA0586 NM_001329943.3 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 14-58482492-ATT-A is Benign according to our data. Variant chr14-58482492-ATT-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3041742.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	NM_001329943.3	MANE Select	c.2945-10_2945-9delTT		intron	N/A	NP_001316872.1
	KIAA0586	NM_001244189.2		c.3104-10_3104-9delTT		intron	N/A	NP_001231118.1
	KIAA0586	NM_001329944.2		c.2945-10_2945-9delTT		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_2945-19delTT		intron	N/A	ENSP00000498929.1
	KIAA0586	ENST00000619416.4	TSL:1	c.2900-20_2900-19delTT		intron	N/A	ENSP00000478083.1
	KIAA0586	ENST00000423743.7	TSL:1	c.2813-20_2813-19delTT		intron	N/A	ENSP00000399427.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 146158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00144 AC: 87 AN: 60246 AF XY: 0.00156

Gnomad AFR exome AF: 0.000956

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00273

Gnomad EAS exome AF: 0.00262

Gnomad FIN exome AF: 0.000564

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00158

GnomAD4 exome AF: 0.000372 AC: 365 AN: 982266 Hom.: 0 AF XY: 0.000407 AC XY: 196 AN XY: 482056

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

African (AFR) AF: 0.000194 AC: 4 AN: 20610

American (AMR) AF: 0.000956 AC: 19 AN: 19866

Ashkenazi Jewish (ASJ) AF: 0.000635 AC: 10 AN: 15746

East Asian (EAS) AF: 0.000474 AC: 13 AN: 27398

South Asian (SAS) AF: 0.00138 AC: 67 AN: 48618

European-Finnish (FIN) AF: 0.000370 AC: 14 AN: 37824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3520

European-Non Finnish (NFE) AF: 0.000294 AC: 226 AN: 768466

Other (OTH) AF: 0.000298 AC: 12 AN: 40218

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 146158 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 71034

African (AFR) AF: 0.00 AC: 0 AN: 39954

American (AMR) AF: 0.00 AC: 0 AN: 14626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3370

East Asian (EAS) AF: 0.00 AC: 0 AN: 5042

South Asian (SAS) AF: 0.00 AC: 0 AN: 4592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66146

Other (OTH) AF: 0.00 AC: 0 AN: 1998

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	KIAA0586-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.028
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;