rs145502517

Variant names:

• chr14-58428196-C-T
• rs145502517
• NM_001329943.3:c.-69C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-58428196-C-T
• chr14-58428196-C-A
• chr14-58428196-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001329943.3(KIAA0586):​c.-69C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,535,014 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (7 hom., cov: 32)
  • Exomes 𝑓: 0.015 (180 hom.)
• Consequence: KIAA0586 NM_001329943.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.176
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 14-58428196-C-T is Benign according to our data. Variant chr14-58428196-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1188490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0103 (1571/152234) while in subpopulation NFE AF = 0.0168 (1146/68014). AF 95% confidence interval is 0.016. There are 7 homozygotes in GnomAd4. There are 728 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	NM_001329943.3	MANE Select	c.-69C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 31	NP_001316872.1	A0A494C171
	KIAA0586	NM_001329943.3	MANE Select	c.-69C>T		5_prime_UTR	Exon 1 of 31	NP_001316872.1	A0A494C171
	KIAA0586	NM_001329944.2		c.-69C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 32	NP_001316873.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.-69C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 31	ENSP00000498929.1	A0A494C171
	KIAA0586	ENST00000261244.9	TSL:1	c.-69C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 30	ENSP00000261244.5	Q9BVV6-2
	KIAA0586	ENST00000652326.2	MANE Select	c.-69C>T		5_prime_UTR	Exon 1 of 31	ENSP00000498929.1	A0A494C171

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1571 AN: 152116 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00969

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00976 AC: 1527 AN: 156464 AF XY: 0.00978

Gnomad AFR exome AF: 0.00229

Gnomad AMR exome AF: 0.00534

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.00915

GnomAD4 exome AF: 0.0149 AC: 20665 AN: 1382780 Hom.: 180 Cov.: 32 AF XY: 0.0144 AC XY: 9839 AN XY: 681514

African (AFR) AF: 0.00240 AC: 73 AN: 30446

American (AMR) AF: 0.00528 AC: 148 AN: 28030

Ashkenazi Jewish (ASJ) AF: 0.000128 AC: 3 AN: 23498

East Asian (EAS) AF: 0.00 AC: 0 AN: 37386

South Asian (SAS) AF: 0.00374 AC: 282 AN: 75498

European-Finnish (FIN) AF: 0.0113 AC: 566 AN: 50230

Middle Eastern (MID) AF: 0.00197 AC: 10 AN: 5074

European-Non Finnish (NFE) AF: 0.0176 AC: 18910 AN: 1075344

Other (OTH) AF: 0.0118 AC: 673 AN: 57274

GnomAD4 genome AF: 0.0103 AC: 1571 AN: 152234 Hom.: 7 Cov.: 32 AF XY: 0.00978 AC XY: 728 AN XY: 74436

African (AFR) AF: 0.00260 AC: 108 AN: 41540

American (AMR) AF: 0.00968 AC: 148 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4832

European-Finnish (FIN) AF: 0.0129 AC: 137 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0168 AC: 1146 AN: 68014

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00761 Hom.: 2

Bravo AF: 0.00952

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.9
DANN	Benign	0.63
PhyloP100		-0.18
PromoterAI		0.0055	Neutral
Mutation Taster		=299/1	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: rs145502517; hg19: chr14-58894914;