14-58488812-T-C

Position:

• chr14-58488812-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (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

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 -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 [Likely_benign]. Clinvar id is 475449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-58488812-T-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIAA0586	NM_001329943.3	c.3719T>C	p.Leu1240Ser	missense_variant	24/31	ENST00000652326.2	NP_001316872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIAA0586	ENST00000652326.2	c.3719T>C	p.Leu1240Ser	missense_variant	24/31		NM_001329943.3	ENSP00000498929	P4

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

GnomAD3 exomes AF: 0.0138 AC: 3442 AN: 249026 Hom.: 31 AF XY: 0.0151 AC XY: 2040 AN XY: 135086

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 SAS exome AF: 0.0228

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

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.00713

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0238

Gnomad4 FIN exome AF: 0.0175

Gnomad4 NFE exome AF: 0.0157

Gnomad4 OTH exome AF: 0.0158

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

Gnomad4 AFR AF: 0.00303

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0240

Gnomad4 FIN AF: 0.0171

Gnomad4 NFE AF: 0.0163

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0144 Hom.: 25

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

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	- -

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	0.076
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.028	.;.;T;T;.;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.52	T;T;T;T;.;T
MetaRNN	Benign	0.0049	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;.;.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.8	N;.;.;.;N;N
REVEL	Benign	0.024
Sift	Benign	0.093	T;.;.;.;T;T
Sift4G	Benign	0.22	T;T;T;T;T;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

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: rs190271845; hg19: chr14-58955530;