14-58482492-ATTT-ATT

Variant names:

• chr14-58482492-AT-A
• rs748594194
• NM_001329943.3:c.2945-9delT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001329943.3(KIAA0586):​c.2945-9delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 888,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.15 (0 hom.)
• Consequence: KIAA0586 NM_001329943.3 intron
• Clinical Significance: Benign criteria provided, single submitter 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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 0 ACMG points.

• PM2: Variant has high frequency in the EAS (0.199) population. However there is too low homozygotes in high coverage region: (expected more than 3616, got 0).
• BP6: Variant 14-58482492-AT-A is Benign according to our data. Variant chr14-58482492-AT-A is described in ClinVar as Benign. ClinVar VariationId is 2934616.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	NM_001329943.3	MANE Select	c.2945-9delT		intron	N/A	NP_001316872.1	A0A494C171
	KIAA0586	NM_001244189.2		c.3104-9delT		intron	N/A	NP_001231118.1	Q9BVV6-3
	KIAA0586	NM_001329944.2		c.2945-9delT		intron	N/A	NP_001316873.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.2945-20delT		intron	N/A	ENSP00000498929.1	A0A494C171
	KIAA0586	ENST00000619416.4	TSL:1	c.2900-20delT		intron	N/A	ENSP00000478083.1	Q9BVV6-1
	KIAA0586	ENST00000423743.7	TSL:1	c.2813-20delT		intron	N/A	ENSP00000399427.3	Q9BVV6-4

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 171 AN: 145756 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000451

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000823

Gnomad ASJ AF: 0.000298

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.000218

Gnomad FIN AF: 0.00428

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00252

GnomAD2 exomes AF: 0.270 AC: 16286 AN: 60246 AF XY: 0.286

Gnomad AFR exome AF: 0.232

Gnomad AMR exome AF: 0.315

Gnomad ASJ exome AF: 0.316

Gnomad EAS exome AF: 0.290

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.152 AC: 113233 AN: 743106 Hom.: 0 Cov.: 0 AF XY: 0.154 AC XY: 56131 AN XY: 364070

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

African (AFR) AF: 0.162 AC: 2444 AN: 15080

American (AMR) AF: 0.184 AC: 2877 AN: 15674

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 2054 AN: 11080

East Asian (EAS) AF: 0.204 AC: 3412 AN: 16692

South Asian (SAS) AF: 0.168 AC: 7048 AN: 41928

European-Finnish (FIN) AF: 0.177 AC: 4675 AN: 26388

Middle Eastern (MID) AF: 0.130 AC: 353 AN: 2722

European-Non Finnish (NFE) AF: 0.146 AC: 85526 AN: 584358

Other (OTH) AF: 0.166 AC: 4844 AN: 29184

⚠️ 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 AF: 0.00117 AC: 171 AN: 145808 Hom.: 0 Cov.: 31 AF XY: 0.00117 AC XY: 83 AN XY: 70858

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

African (AFR) AF: 0.000450 AC: 18 AN: 40004

American (AMR) AF: 0.000822 AC: 12 AN: 14598

Ashkenazi Jewish (ASJ) AF: 0.000298 AC: 1 AN: 3358

East Asian (EAS) AF: 0.000199 AC: 1 AN: 5024

South Asian (SAS) AF: 0.000219 AC: 1 AN: 4574

European-Finnish (FIN) AF: 0.00428 AC: 39 AN: 9118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00143 AC: 94 AN: 65938

Other (OTH) AF: 0.00249 AC: 5 AN: 2008

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

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
PhyloP100		-0.028
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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; COSMIC: COSV54173838;