rs61735931

Variant names:

• chr14-58442717-T-C
• rs61735931
• NM_001329943.3:c.422T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 8P and 12B. PVS1 BP6_Very_Strong BS2

The NM_001244193.2(KIAA0586):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00673 in 1,567,602 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (51 hom.)
• Consequence: KIAA0586 NM_001244193.2 start_lost
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.497
• Publications: 9 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 -4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 8 pathogenic variants. Next in-frame start position is after 107 codons. Genomic position: 58444107. Lost 0.079 part of the original CDS.
• BP6: Variant 14-58442717-T-C is Benign according to our data. Variant chr14-58442717-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244193.2. 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.422T>C	p.Met141Thr	missense	Exon 5 of 31	NP_001316872.1	A0A494C171
	KIAA0586	NM_001244193.2		c.2T>C	p.Met1?	start_lost	Exon 2 of 27	NP_001231122.1
	KIAA0586	NM_001244189.2		c.581T>C	p.Met194Thr	missense	Exon 7 of 34	NP_001231118.1	Q9BVV6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.422T>C	p.Met141Thr	missense	Exon 5 of 31	ENSP00000498929.1	A0A494C171
	KIAA0586	ENST00000619416.4	TSL:1	c.377T>C	p.Met126Thr	missense	Exon 6 of 32	ENSP00000478083.1	Q9BVV6-1
	KIAA0586	ENST00000423743.7	TSL:1	c.290T>C	p.Met97Thr	missense	Exon 6 of 32	ENSP00000399427.3	Q9BVV6-4

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 790 AN: 152196 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00810

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00509 AC: 939 AN: 184644 AF XY: 0.00490

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00956

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00519

Gnomad NFE exome AF: 0.00765

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00690 AC: 9766 AN: 1415288 Hom.: 51 Cov.: 29 AF XY: 0.00682 AC XY: 4774 AN XY: 699890

African (AFR) AF: 0.00102 AC: 33 AN: 32424

American (AMR) AF: 0.00349 AC: 130 AN: 37202

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 272 AN: 25290

East Asian (EAS) AF: 0.00 AC: 0 AN: 37930

South Asian (SAS) AF: 0.00137 AC: 110 AN: 80386

European-Finnish (FIN) AF: 0.00617 AC: 314 AN: 50884

Middle Eastern (MID) AF: 0.00210 AC: 12 AN: 5706

European-Non Finnish (NFE) AF: 0.00786 AC: 8541 AN: 1086730

Other (OTH) AF: 0.00603 AC: 354 AN: 58736

GnomAD4 genome AF: 0.00519 AC: 790 AN: 152314 Hom.: 3 Cov.: 33 AF XY: 0.00458 AC XY: 341 AN XY: 74472

African (AFR) AF: 0.00123 AC: 51 AN: 41586

American (AMR) AF: 0.00425 AC: 65 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00481 AC: 51 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00810 AC: 551 AN: 68032

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00701 Hom.: 13

Bravo AF: 0.00484

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00136 AC: 5

ESP6500EA AF: 0.00769 AC: 63

ExAC AF: 0.00424 AC: 506

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.50
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.035
Sift	Benign	0.14	T
Sift4G	Benign	0.18	T
Polyphen		0.0030	B
Vest4		0.32
MVP		0.42
MPC		0.036
ClinPred		0.0049	T
GERP RS		1.3
Varity_R		0.090
gMVP		0.035
Mutation Taster		=95/5	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: rs61735931; hg19: chr14-58909435;