rs190271845

Variant names:

• chr14-58488812-T-C
• rs190271845
• NM_001329943.3:c.3719T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-58488812-T-C
• chr14-58488812-T-A

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.3719T>C​(p.Leu1240Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,613,894 control chromosomes in the GnomAD database, including 224 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 0.012 (18 hom., cov: 32)
  • Exomes 𝑓: 0.015 (206 hom.)
• Consequence: KIAA0586 NM_001329943.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.451
• Publications: 10 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 (MetaRNN=0.0049393475).
• BP6: Variant 14-58488812-T-C is Benign according to our data. Variant chr14-58488812-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0117 (1789/152274) while in subpopulation SAS AF = 0.024 (116/4828). AF 95% confidence interval is 0.0205. There are 18 homozygotes in GnomAd4. There are 907 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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.3719T>C	p.Leu1240Ser	missense	Exon 24 of 31	NP_001316872.1	A0A494C171
	KIAA0586	NM_001244189.2		c.3878T>C	p.Leu1293Ser	missense	Exon 26 of 34	NP_001231118.1	Q9BVV6-3
	KIAA0586	NM_001329944.2		c.3719T>C	p.Leu1240Ser	missense	Exon 24 of 32	NP_001316873.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.3719T>C	p.Leu1240Ser	missense	Exon 24 of 31	ENSP00000498929.1	A0A494C171
	KIAA0586	ENST00000619416.4	TSL:1	c.3674T>C	p.Leu1225Ser	missense	Exon 25 of 32	ENSP00000478083.1	Q9BVV6-1
	KIAA0586	ENST00000423743.7	TSL:1	c.3587T>C	p.Leu1196Ser	missense	Exon 25 of 32	ENSP00000399427.3	Q9BVV6-4

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1789 AN: 152156 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0138 AC: 3442 AN: 249026 AF XY: 0.0151

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00669

Gnomad ASJ exome AF: 0.00935

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0173

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.0187

GnomAD4 exome AF: 0.0153 AC: 22362 AN: 1461620 Hom.: 206 Cov.: 31 AF XY: 0.0156 AC XY: 11349 AN XY: 727092

African (AFR) AF: 0.00230 AC: 77 AN: 33478

American (AMR) AF: 0.00713 AC: 319 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 296 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.0238 AC: 2056 AN: 86254

European-Finnish (FIN) AF: 0.0175 AC: 937 AN: 53402

Middle Eastern (MID) AF: 0.0380 AC: 219 AN: 5768

European-Non Finnish (NFE) AF: 0.0157 AC: 17501 AN: 1111800

Other (OTH) AF: 0.0158 AC: 956 AN: 60370

GnomAD4 genome AF: 0.0117 AC: 1789 AN: 152274 Hom.: 18 Cov.: 32 AF XY: 0.0122 AC XY: 907 AN XY: 74456

African (AFR) AF: 0.00303 AC: 126 AN: 41556

American (AMR) AF: 0.0114 AC: 175 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0240 AC: 116 AN: 4828

European-Finnish (FIN) AF: 0.0171 AC: 182 AN: 10614

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0163 AC: 1110 AN: 68014

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0142 Hom.: 55

Bravo AF: 0.0110

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00215 AC: 8

ESP6500EA AF: 0.0128 AC: 105

ExAC AF: 0.0144 AC: 1735

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0164

EpiControl AF: 0.0175

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.45
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.024
Sift	Benign	0.093	T
Sift4G	Benign	0.22	T
Polyphen		0.019	B
Vest4		0.14
MPC		0.024
ClinPred		0.0031	T
GERP RS		1.5
Varity_R		0.051
gMVP		0.10
Mutation Taster		=98/2	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: rs190271845; hg19: chr14-58955530;