rs3783697

Positions:

• chr14-58492205-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001329943.3(KIAA0586):​c.3920A>G​(p.Asp1307Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00616 in 1,550,530 control chromosomes in the GnomAD database, including 407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (367 hom.)
• Consequence: KIAA0586 NM_001329943.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.00

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=0.002554804).
• BP6: Variant 14-58492205-A-G is Benign according to our data. Variant chr14-58492205-A-G is described in ClinVar as [Benign]. Clinvar id is 475450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0875 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0586	NM_001329943.3	c.3920A>G	p.Asp1307Gly	missense_variant	26/31	ENST00000652326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0586	ENST00000652326.2	c.3920A>G	p.Asp1307Gly	missense_variant	26/31		NM_001329943.3	P4

Frequencies

GnomAD3 genomes AF: 0.00925 AC: 1408 AN: 152220 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0475

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.0944

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.0243 AC: 3839 AN: 157738 Hom.: 199 AF XY: 0.0209 AC XY: 1743 AN XY: 83284

Gnomad AFR exome AF: 0.00171

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.00411

Gnomad EAS exome AF: 0.0949

Gnomad SAS exome AF: 0.00537

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000589

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.00583 AC: 8147 AN: 1398192 Hom.: 367 Cov.: 30 AF XY: 0.00559 AC XY: 3857 AN XY: 689646

Gnomad4 AFR exome AF: 0.000919

Gnomad4 AMR exome AF: 0.0918

Gnomad4 ASJ exome AF: 0.00397

Gnomad4 EAS exome AF: 0.0961

Gnomad4 SAS exome AF: 0.00483

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000400

Gnomad4 OTH exome AF: 0.00886

GnomAD4 genome AF: 0.00924 AC: 1407 AN: 152338 Hom.: 40 Cov.: 32 AF XY: 0.0104 AC XY: 777 AN XY: 74514

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.0474

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.0944

Gnomad4 SAS AF: 0.00766

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00556 Hom.: 59

Bravo AF: 0.0159

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000720 AC: 3

ESP6500EA AF: 0.000973 AC: 8

ExAC AF: 0.00684 AC: 577

Asia WGS AF: 0.0380 AC: 132 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 20, 2018

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D;D;D;D;.;D
MetaRNN	Benign	0.0026	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-4.7	D;.;.;.;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0060	D;.;.;.;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D
Polyphen		0.96	.;.;.;D;.;.
Vest4		0.31
MPC		0.12
ClinPred		0.025	T
GERP RS		5.1
Varity_R		0.39
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3783697; hg19: chr14-58958923; COSMIC: COSV54172293;