rs61735931

Positions:

• chr14-58442717-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001329943.3(KIAA0586):​c.422T>C​(p.Met141Thr) variant causes a missense 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. 14/20 in silico tools predict 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_001329943.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.497

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061211884).
• BP6: Variant 14-58442717-T-C is Benign according to our data. Variant chr14-58442717-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 377258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIAA0586	NM_001329943.3	c.422T>C	p.Met141Thr	missense_variant	5/31	ENST00000652326.2	NP_001316872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIAA0586	ENST00000652326.2	c.422T>C	p.Met141Thr	missense_variant	5/31		NM_001329943.3	ENSP00000498929	P4

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

GnomAD3 exomes AF: 0.00509 AC: 939 AN: 184644 Hom.: 6 AF XY: 0.00490 AC XY: 482 AN XY: 98274

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 SAS exome AF: 0.00162

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

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00349

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00617

Gnomad4 NFE exome AF: 0.00786

Gnomad4 OTH exome AF: 0.00603

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

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00481

Gnomad4 NFE AF: 0.00810

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00729 Hom.: 11

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

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KIAA0586: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2019	- -

Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T;.;T;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.65	T;T;T;T;.;T;T;T
MetaRNN	Benign	0.0061	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;.;.;L;.;.;.;.
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.5	N;.;.;.;N;N;N;N
REVEL	Benign	0.035
Sift	Benign	0.14	T;.;.;.;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T;T;T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs61735931; hg19: chr14-58909435;