rs144456198

Variant names:

• chr14-58450591-A-T
• rs144456198
• NM_001329943.3:c.974A>T

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.974A>T​(p.Glu325Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,602,056 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E325E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (13 hom.)
• Consequence: KIAA0586 NM_001329943.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.10
• Publications: 8 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=0.0041021705).
• BP6: Variant 14-58450591-A-T is Benign according to our data. Variant chr14-58450591-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 542191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.974A>T	p.Glu325Val	missense	Exon 8 of 31	NP_001316872.1
	KIAA0586	NM_001244189.2		c.1133A>T	p.Glu378Val	missense	Exon 10 of 34	NP_001231118.1
	KIAA0586	NM_001329944.2		c.974A>T	p.Glu325Val	missense	Exon 8 of 32	NP_001316873.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.974A>T	p.Glu325Val	missense	Exon 8 of 31	ENSP00000498929.1
	KIAA0586	ENST00000619416.4	TSL:1	c.929A>T	p.Glu310Val	missense	Exon 9 of 32	ENSP00000478083.1
	KIAA0586	ENST00000423743.7	TSL:1	c.842A>T	p.Glu281Val	missense	Exon 9 of 32	ENSP00000399427.3

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 299 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00222 AC: 531 AN: 239022 AF XY: 0.00222

Gnomad AFR exome AF: 0.000461

Gnomad AMR exome AF: 0.00435

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000373

Gnomad NFE exome AF: 0.00325

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00274 AC: 3979 AN: 1449720 Hom.: 13 Cov.: 29 AF XY: 0.00267 AC XY: 1927 AN XY: 721234

African (AFR) AF: 0.000520 AC: 17 AN: 32676

American (AMR) AF: 0.00442 AC: 182 AN: 41134

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25812

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.0000359 AC: 3 AN: 83646

European-Finnish (FIN) AF: 0.000639 AC: 34 AN: 53224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00325 AC: 3605 AN: 1107896

Other (OTH) AF: 0.00228 AC: 137 AN: 59968

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00174 AC XY: 130 AN XY: 74502

African (AFR) AF: 0.000457 AC: 19 AN: 41574

American (AMR) AF: 0.00451 AC: 69 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00269 AC: 183 AN: 68034

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00256 Hom.: 1

Bravo AF: 0.00266

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000837 AC: 3

ESP6500EA AF: 0.00307 AC: 25

ExAC AF: 0.00209 AC: 252

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00284

EpiControl AF: 0.00314

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	Inborn genetic diseases (1)
-	-	1	Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly (1)
-	-	1	KIAA0586-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.058
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.047	D
Polyphen		0.0020	B
Vest4		0.21
MVP		0.62
MPC		0.021
ClinPred		0.025	T
GERP RS		2.1
Varity_R		0.068
gMVP		0.30
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs144456198; hg19: chr14-58917309;