14-58482492-ATTT-ATTTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001329943.3(KIAA0586):​c.2945-9dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,076,144 control chromosomes in the GnomAD database, including 21 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (9 hom., cov: 31)
  • Exomes 𝑓: 0.043 (12 hom.)
• Consequence: KIAA0586 NM_001329943.3 splice_region, 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: 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 14-58482492-A-AT is Benign according to our data. Variant chr14-58482492-A-AT is described in ClinVar as Benign. ClinVar VariationId is 445610.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0111 (1615/146144) while in subpopulation NFE AF = 0.0168 (1109/66106). AF 95% confidence interval is 0.016. There are 9 homozygotes in GnomAd4. There are 787 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

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.2945-9dupT		splice_region intron	N/A	NP_001316872.1
	KIAA0586	NM_001244189.2		c.3104-9dupT		splice_region intron	N/A	NP_001231118.1
	KIAA0586	NM_001329944.2		c.2945-9dupT		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_2945-20insT		intron	N/A	ENSP00000498929.1
	KIAA0586	ENST00000619416.4	TSL:1	c.2900-21_2900-20insT		intron	N/A	ENSP00000478083.1
	KIAA0586	ENST00000423743.7	TSL:1	c.2813-21_2813-20insT		intron	N/A	ENSP00000399427.3

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1609 AN: 146090 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00373

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00298

Gnomad SAS AF: 0.00305

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00649

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.00801

GnomAD2 exomes AF: 0.0551 AC: 3320 AN: 60246 AF XY: 0.0567

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.0586

Gnomad ASJ exome AF: 0.0770

Gnomad EAS exome AF: 0.0421

Gnomad FIN exome AF: 0.0510

Gnomad NFE exome AF: 0.0598

Gnomad OTH exome AF: 0.0694

GnomAD4 exome AF: 0.0433 AC: 40240 AN: 930000 Hom.: 12 Cov.: 0 AF XY: 0.0429 AC XY: 19597 AN XY: 457186

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

African (AFR) AF: 0.0260 AC: 505 AN: 19432

American (AMR) AF: 0.0262 AC: 506 AN: 19334

Ashkenazi Jewish (ASJ) AF: 0.0385 AC: 577 AN: 15002

East Asian (EAS) AF: 0.0165 AC: 429 AN: 26062

South Asian (SAS) AF: 0.0328 AC: 1551 AN: 47278

European-Finnish (FIN) AF: 0.0315 AC: 1143 AN: 36340

Middle Eastern (MID) AF: 0.0174 AC: 59 AN: 3390

European-Non Finnish (NFE) AF: 0.0468 AC: 33956 AN: 725142

Other (OTH) AF: 0.0398 AC: 1514 AN: 38020

⚠️ 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: 0.0111 AC: 1615 AN: 146144 Hom.: 9 Cov.: 31 AF XY: 0.0111 AC XY: 787 AN XY: 71064

African (AFR) AF: 0.00375 AC: 150 AN: 40034

American (AMR) AF: 0.00759 AC: 111 AN: 14634

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 67 AN: 3370

East Asian (EAS) AF: 0.00298 AC: 15 AN: 5028

South Asian (SAS) AF: 0.00328 AC: 15 AN: 4576

European-Finnish (FIN) AF: 0.0136 AC: 125 AN: 9194

Middle Eastern (MID) AF: 0.00704 AC: 2 AN: 284

European-Non Finnish (NFE) AF: 0.0168 AC: 1109 AN: 66106

Other (OTH) AF: 0.00991 AC: 20 AN: 2018

Alfa AF: 0.00475 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (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: COSV54170728;