rs11611

Variant names:

• chr14-58540102-T-C
• rs11611
• NM_001329943.3:c.4461T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001244189.2(KIAA0586):​c.4620T>C​(p.Ile1540Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00479 in 1,563,672 control chromosomes in the GnomAD database, including 209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (112 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (97 hom.)
• Consequence: KIAA0586 NM_001244189.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.927
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-58540102-T-C is Benign according to our data. Variant chr14-58540102-T-C is described in ClinVar as Benign. ClinVar VariationId is 475453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.927 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.065 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244189.2. 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.4461T>C	p.Ile1487Ile	synonymous	Exon 30 of 31	NP_001316872.1
	KIAA0586	NM_001244189.2		c.4620T>C	p.Ile1540Ile	synonymous	Exon 32 of 34	NP_001231118.1
	KIAA0586	NM_001329944.2		c.4461T>C	p.Ile1487Ile	synonymous	Exon 30 of 32	NP_001316873.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.4461T>C	p.Ile1487Ile	synonymous	Exon 30 of 31	ENSP00000498929.1
	KIAA0586	ENST00000619416.4	TSL:1	c.4416T>C	p.Ile1472Ile	synonymous	Exon 31 of 32	ENSP00000478083.1
	KIAA0586	ENST00000423743.7	TSL:1	c.4329T>C	p.Ile1443Ile	synonymous	Exon 31 of 32	ENSP00000399427.3

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3058 AN: 152194 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0665

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00705 AC: 1294 AN: 183502 AF XY: 0.00631

Gnomad AFR exome AF: 0.0684

Gnomad AMR exome AF: 0.00409

Gnomad ASJ exome AF: 0.00302

Gnomad EAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000619

Gnomad OTH exome AF: 0.00468

GnomAD4 exome AF: 0.00311 AC: 4396 AN: 1411360 Hom.: 97 Cov.: 26 AF XY: 0.00317 AC XY: 2213 AN XY: 697620

African (AFR) AF: 0.0672 AC: 2164 AN: 32184

American (AMR) AF: 0.00448 AC: 170 AN: 37976

Ashkenazi Jewish (ASJ) AF: 0.00308 AC: 78 AN: 25358

East Asian (EAS) AF: 0.0115 AC: 437 AN: 37848

South Asian (SAS) AF: 0.00847 AC: 678 AN: 80008

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50574

Middle Eastern (MID) AF: 0.00666 AC: 38 AN: 5706

European-Non Finnish (NFE) AF: 0.000350 AC: 379 AN: 1083136

Other (OTH) AF: 0.00770 AC: 451 AN: 58570

GnomAD4 genome AF: 0.0203 AC: 3093 AN: 152312 Hom.: 112 Cov.: 32 AF XY: 0.0196 AC XY: 1461 AN XY: 74474

African (AFR) AF: 0.0671 AC: 2788 AN: 41552

American (AMR) AF: 0.00739 AC: 113 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.0110 AC: 57 AN: 5192

South Asian (SAS) AF: 0.00891 AC: 43 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68030

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.00787 Hom.: 55

Bravo AF: 0.0224

Asia WGS AF: 0.0260 AC: 90 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: 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
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.11
DANN	Benign	0.32
PhyloP100		-0.93
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs11611; hg19: chr14-59006820;