rs199537542

Variant names:

• chr14-58482571-C-A
• rs199537542
• NM_001329943.3:c.3003C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001329943.3(KIAA0586):​c.3003C>A​(p.Asn1001Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,599,838 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: KIAA0586 NM_001329943.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 0.331
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26135385).

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.3003C>A	p.Asn1001Lys	missense	Exon 21 of 31	NP_001316872.1	A0A494C171
	KIAA0586	NM_001244189.2		c.3162C>A	p.Asn1054Lys	missense	Exon 23 of 34	NP_001231118.1	Q9BVV6-3
	KIAA0586	NM_001329944.2		c.3003C>A	p.Asn1001Lys	missense	Exon 21 of 32	NP_001316873.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.3003C>A	p.Asn1001Lys	missense	Exon 21 of 31	ENSP00000498929.1	A0A494C171
	KIAA0586	ENST00000619416.4	TSL:1	c.2958C>A	p.Asn986Lys	missense	Exon 22 of 32	ENSP00000478083.1	Q9BVV6-1
	KIAA0586	ENST00000423743.7	TSL:1	c.2871C>A	p.Asn957Lys	missense	Exon 22 of 32	ENSP00000399427.3	Q9BVV6-4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 151816 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000162 AC: 39 AN: 241288 AF XY: 0.000160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000257 AC: 372 AN: 1448022 Hom.: 1 Cov.: 32 AF XY: 0.000235 AC XY: 169 AN XY: 719998

African (AFR) AF: 0.0000304 AC: 1 AN: 32860

American (AMR) AF: 0.000161 AC: 7 AN: 43578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25816

East Asian (EAS) AF: 0.00 AC: 0 AN: 38808

South Asian (SAS) AF: 0.00 AC: 0 AN: 84240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.000315 AC: 348 AN: 1104298

Other (OTH) AF: 0.000268 AC: 16 AN: 59646

GnomAD4 genome AF: 0.000184 AC: 28 AN: 151816 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74114

African (AFR) AF: 0.0000726 AC: 3 AN: 41306

American (AMR) AF: 0.0000656 AC: 1 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000255 Hom.: 0

Bravo AF: 0.000185

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000486 AC: 4

ExAC AF: 0.000124 AC: 15

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly (2)
-	1	1	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.33
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.15
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.023	D
Polyphen		0.93	P
Vest4		0.56
MutPred		0.47		Gain of catalytic residue at N986 (P = 0)
MVP		0.38
MPC		0.059
ClinPred		0.33	T
GERP RS		-0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.20
Mutation Taster		=89/11	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: rs199537542; hg19: chr14-58949289; COSMIC: COSV106093962;