rs17094553

chr14-58465832-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001329943.3(KIAA0586):c.2060-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,565,186 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: KIAA0586 NM_001329943.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001021
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.43

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-58465832-T-C is Benign according to our data. Variant chr14-58465832-T-C is described in ClinVar as [Benign]. Clinvar id is 475442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0113 (1720/152322) while in subpopulation AFR AF= 0.0382 (1587/41558). AF 95% confidence interval is 0.0366. There are 37 homozygotes in gnomad4. There are 781 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0586	NM_001329943.3	c.2060-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000652326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0586	ENST00000652326.2	c.2060-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001329943.3	P4

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1715 AN: 152204 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00288 AC: 670 AN: 232684 Hom.: 11 AF XY: 0.00221 AC XY: 279 AN XY: 126234

Gnomad AFR exome AF: 0.0375

Gnomad AMR exome AF: 0.00279

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000752

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000740

Gnomad OTH exome AF: 0.00144

GnomAD4 exome AF: 0.00109 AC: 1541 AN: 1412864 Hom.: 23 Cov.: 25 AF XY: 0.000968 AC XY: 681 AN XY: 703258

Gnomad4 AFR exome AF: 0.0364

Gnomad4 AMR exome AF: 0.00299

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000862

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000547

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.0113 AC: 1720 AN: 152322 Hom.: 37 Cov.: 32 AF XY: 0.0105 AC XY: 781 AN XY: 74490

Gnomad4 AFR AF: 0.0382

Gnomad4 AMR AF: 0.00614

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00513 Hom.: 2

Bravo AF: 0.0130

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000120

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 20, 2019

- -

Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.39
Dann	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000010
dbscSNV1_RF	Benign	0.034
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

Publications

LitVar

Other links and lift over

dbSNP: rs17094553; hg19: chr14-58932550;