rs140565291

Variant names:

• chr14-58487145-A-C
• rs140565291
• NM_001329943.3:c.3283A>C

Your query was ambiguous. Multiple possible variants found:

• chr14-58487145-A-C
• chr14-58487145-A-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_001329943.3(KIAA0586):​c.3283A>C​(p.Lys1095Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,611,814 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (12 hom.)
• Consequence: KIAA0586 NM_001329943.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.599
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059957504).
• BP6: Variant 14-58487145-A-C is Benign according to our data. Variant chr14-58487145-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.3283A>C	p.Lys1095Gln	missense	Exon 22 of 31	NP_001316872.1
	KIAA0586	NM_001244189.2		c.3442A>C	p.Lys1148Gln	missense	Exon 24 of 34	NP_001231118.1
	KIAA0586	NM_001329944.2		c.3283A>C	p.Lys1095Gln	missense	Exon 22 of 32	NP_001316873.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.3283A>C	p.Lys1095Gln	missense	Exon 22 of 31	ENSP00000498929.1
	KIAA0586	ENST00000619416.4	TSL:1	c.3238A>C	p.Lys1080Gln	missense	Exon 23 of 32	ENSP00000478083.1
	KIAA0586	ENST00000423743.7	TSL:1	c.3151A>C	p.Lys1051Gln	missense	Exon 23 of 32	ENSP00000399427.3

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 512 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00999

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00202 AC: 496 AN: 246088 AF XY: 0.00235

Gnomad AFR exome AF: 0.00958

Gnomad AMR exome AF: 0.00158

Gnomad ASJ exome AF: 0.00221

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000445

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.000926 AC: 1352 AN: 1459512 Hom.: 12 Cov.: 31 AF XY: 0.00117 AC XY: 847 AN XY: 725906

African (AFR) AF: 0.00914 AC: 305 AN: 33380

American (AMR) AF: 0.00147 AC: 65 AN: 44174

Ashkenazi Jewish (ASJ) AF: 0.00188 AC: 49 AN: 26072

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.00741 AC: 634 AN: 85512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5762

European-Non Finnish (NFE) AF: 0.000157 AC: 175 AN: 1111228

Other (OTH) AF: 0.00164 AC: 99 AN: 60304

GnomAD4 genome AF: 0.00339 AC: 516 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00357 AC XY: 266 AN XY: 74482

African (AFR) AF: 0.0100 AC: 417 AN: 41562

American (AMR) AF: 0.00170 AC: 26 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00135 Hom.: 5

Bravo AF: 0.00383

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00982 AC: 36

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.00227 AC: 274

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Joubert syndrome 23 (1)
-	-	1	Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly (1)
-	-	1	KIAA0586-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.1
DANN	Benign	0.82
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.60
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.021
Sift	Benign	0.15	T
Sift4G	Benign	0.17	T
Polyphen		0.19	B
Vest4		0.21
MVP		0.23
MPC		0.088
ClinPred		0.012	T
GERP RS		1.3
Varity_R		0.058
gMVP		0.12
Mutation Taster		=99/1	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: rs140565291; hg19: chr14-58953863; COSMIC: COSV107200997; COSMIC: COSV107200997;