14-58428364-G-T

Variant names:

• chr14-58428364-G-T
• rs186659284
• NM_001329943.3:c.100G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001329943.3(KIAA0586):​c.100G>T​(p.Val34Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000967 in 1,613,964 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V34I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (14 hom.)
• Consequence: KIAA0586 NM_001329943.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.408
• Publications: 1 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• short-rib thoracic dysplasia 14 with polydactyly

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027813017).
• BP6: Variant 14-58428364-G-T is Benign according to our data. Variant chr14-58428364-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00216 (329/152286) while in subpopulation AMR AF = 0.0204 (312/15292). AF 95% confidence interval is 0.0185. There are 6 homozygotes in GnomAd4. There are 174 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329943.3. 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.100G>T	p.Val34Phe	missense	Exon 1 of 31	NP_001316872.1	A0A494C171
	KIAA0586	NM_001244189.2		c.136G>T	p.Val46Phe	missense	Exon 2 of 34	NP_001231118.1	Q9BVV6-3
	KIAA0586	NM_001329944.2		c.100G>T	p.Val34Phe	missense	Exon 1 of 32	NP_001316873.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.100G>T	p.Val34Phe	missense	Exon 1 of 31	ENSP00000498929.1	A0A494C171
	KIAA0586	ENST00000619416.4	TSL:1	c.55G>T	p.Val19Phe	missense	Exon 2 of 32	ENSP00000478083.1	Q9BVV6-1
	KIAA0586	ENST00000261244.9	TSL:1	c.100G>T	p.Val34Phe	missense	Exon 1 of 30	ENSP00000261244.5	Q9BVV6-2

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152168 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00398 AC: 991 AN: 249266 AF XY: 0.00299

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0278

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00413

GnomAD4 exome AF: 0.000842 AC: 1231 AN: 1461678 Hom.: 14 Cov.: 32 AF XY: 0.000748 AC XY: 544 AN XY: 727122

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.0262 AC: 1172 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111850

Other (OTH) AF: 0.000663 AC: 40 AN: 60370

GnomAD4 genome AF: 0.00216 AC: 329 AN: 152286 Hom.: 6 Cov.: 32 AF XY: 0.00234 AC XY: 174 AN XY: 74474

African (AFR) AF: 0.000313 AC: 13 AN: 41550

American (AMR) AF: 0.0204 AC: 312 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000388 Hom.: 0

Bravo AF: 0.00309

ESP6500AA AF: 0.000248 AC: 1

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00285 AC: 345

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.41
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.042
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.015	D
Polyphen		0.15	B
Vest4		0.28
MVP		0.44
MPC		0.086
ClinPred		0.075	T
GERP RS		-2.4
PromoterAI		0.025	Neutral
Varity_R		0.14
gMVP		0.085
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs186659284; hg19: chr14-58895082;