rs776901858

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_004311.4(ARL3):c.445C>T(p.Arg149Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,613,992 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R149H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

ARL3
NM_004311.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.76

Variant links:

Genes affected

ARL3 (HGNC:694): (ADP ribosylation factor like GTPase 3) Enables GDP binding activity; GTP binding activity; and microtubule binding activity. Involved in several processes, including cilium assembly; protein localization to cilium; and small GTPase mediated signal transduction. Acts upstream of or within post-Golgi vesicle-mediated transport. Located in several cellular components, including microtubule cytoskeleton; midbody; and photoreceptor connecting cilium. Implicated in Joubert syndrome and retinitis pigmentosa 83. [provided by Alliance of Genome Resources, Apr 2022]

ARL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a chain ADP-ribosylation factor-like protein 3 (size 180) in uniprot entity ARL3_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_004311.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-102685871-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.863

PP5

Variant 10-102685872-G-A is Pathogenic according to our data. Variant chr10-102685872-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 587372.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-102685872-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARL3	NM_004311.4 link	c.445C>T	p.Arg149Cys	missense_variant	Exon 5 of 6	ENST00000260746.6	NP_004302.1	P36405
ARL3	XM_017016260.2 link	c.445C>T	p.Arg149Cys	missense_variant	Exon 5 of 6		XP_016871749.1	P36405

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARL3	ENST00000260746.6 link	c.445C>T	p.Arg149Cys	missense_variant	Exon 5 of 6	1	NM_004311.4	ENSP00000260746.4		P36405

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251366

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Joubert syndrome 35

Pathogenic:1

Oct 30, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Mar 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 149 of the ARL3 protein (p.Arg149Cys). This variant is present in population databases (rs776901858, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive Joubert syndrome (PMID: 30269812). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 587372). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg149 amino acid residue in ARL3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30269812). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

2.9

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-6.4

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.73

MutPred

0.63

Loss of MoRF binding (P = 0.0916);

MVP

0.82

MPC

1.7

ClinPred

0.95

GERP RS

5.0

Varity_R

0.67

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over