14-58514384-G-A

Variant names:

• chr14-58514384-G-A
• rs3783698
• NM_001329943.3:c.4429+1757G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001329943.3(KIAA0586):​c.4429+1757G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 151,844 control chromosomes in the GnomAD database, including 5,470 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (5470 hom., cov: 32)
• Consequence: KIAA0586 NM_001329943.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.701
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

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.4429+1757G>A		intron	N/A	NP_001316872.1
	KIAA0586	NM_001364700.1		c.*157G>A		3_prime_UTR	Exon 30 of 30	NP_001351629.1
	KIAA0586	NM_001244189.2		c.4588+1757G>A		intron	N/A	NP_001231118.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.4429+1757G>A		intron	N/A	ENSP00000498929.1
	KIAA0586	ENST00000619416.4	TSL:1	c.4384+1757G>A		intron	N/A	ENSP00000478083.1
	KIAA0586	ENST00000423743.7	TSL:1	c.4297+1757G>A		intron	N/A	ENSP00000399427.3

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40547 AN: 151726 Hom.: 5468 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.255

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.267 AC: 40541 AN: 151844 Hom.: 5470 Cov.: 32 AF XY: 0.268 AC XY: 19915 AN XY: 74200

African (AFR) AF: 0.220 AC: 9139 AN: 41468

American (AMR) AF: 0.258 AC: 3931 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 946 AN: 3460

East Asian (EAS) AF: 0.364 AC: 1878 AN: 5164

South Asian (SAS) AF: 0.338 AC: 1627 AN: 4818

European-Finnish (FIN) AF: 0.285 AC: 3008 AN: 10544

Middle Eastern (MID) AF: 0.207 AC: 60 AN: 290

European-Non Finnish (NFE) AF: 0.282 AC: 19111 AN: 67834

Other (OTH) AF: 0.255 AC: 536 AN: 2104

Alfa AF: 0.281 Hom.: 4283

Bravo AF: 0.258

Asia WGS AF: 0.333 AC: 1158 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.7
DANN	Benign	0.39
PhyloP100		0.70
Mutation Taster		=100/0	polymorphism (auto)

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: rs3783698; hg19: chr14-58981102;