NM_001174150.2:c.599G>A

Variant names:

• chr3-94036664-G-A
• rs764109067
• NM_001174150.2:c.599G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001174150.2(ARL13B):​c.599G>A​(p.Arg200His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R200C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ARL13B NM_001174150.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.60
• Publications: 4 publications found

Genes affected

ARL13B (HGNC:25419): (ADP ribosylation factor like GTPase 13B) This gene encodes a member of the ADP-ribosylation factor-like family. The encoded protein is a small GTPase that contains both N-terminal and C-terminal guanine nucleotide-binding motifs. This protein is localized in the cilia and plays a role in cilia formation and in maintenance of cilia. Mutations in this gene are the cause of Joubert syndrome 8. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

ARL13B Gene-Disease associations (from GenCC):

• Joubert syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Joubert syndrome 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-94036663-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86
• PP5: Variant 3-94036664-G-A is Pathogenic according to our data. Variant chr3-94036664-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 266096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174150.2. 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
	ARL13B	NM_001174150.2	MANE Select	c.599G>A	p.Arg200His	missense	Exon 5 of 10	NP_001167621.1	Q3SXY8-1
	ARL13B	NM_182896.3		c.599G>A	p.Arg200His	missense	Exon 5 of 11	NP_878899.1	Q3SXY8-1
	ARL13B	NM_001321328.2		c.554G>A	p.Arg185His	missense	Exon 6 of 11	NP_001308257.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL13B	ENST00000394222.8	TSL:1 MANE Select	c.599G>A	p.Arg200His	missense	Exon 5 of 10	ENSP00000377769.3	Q3SXY8-1
	ARL13B	ENST00000471138.5	TSL:1	c.599G>A	p.Arg200His	missense	Exon 5 of 11	ENSP00000420780.1	Q3SXY8-1
	ARL13B	ENST00000535334.5	TSL:1	c.290G>A	p.Arg97His	missense	Exon 4 of 9	ENSP00000445145.1	Q3SXY8-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Joubert syndrome 8 (4)
2	-	-	not provided (2)
1	-	-	Joubert syndrome and related disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.57		Gain of loop (P = 0.0312)
MVP		0.97
MPC		0.48
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.64
gMVP		0.70
Mutation Taster		=145/155	disease causing (ClinVar)

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: rs764109067; hg19: chr3-93755508;