chr10-102685845-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_004311.4(ARL3):ā€‹c.472T>Gā€‹(p.Cys158Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,330 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 Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

ARL3
NM_004311.4 missense

Scores

11
7
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.32
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARL3NM_004311.4 linkc.472T>G p.Cys158Gly missense_variant 5/6 ENST00000260746.6 NP_004302.1 P36405
ARL3XM_017016260.2 linkc.472T>G p.Cys158Gly missense_variant 5/6 XP_016871749.1 P36405

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARL3ENST00000260746.6 linkc.472T>G p.Cys158Gly missense_variant 5/61 NM_004311.4 ENSP00000260746.4 P36405

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
250628
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135460
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461330
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727006
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000897
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Joubert syndrome 35;C4748536:Retinitis pigmentosa 83 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 04, 2022- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 22, 2023This variant is present in population databases (rs778332463, gnomAD 0.01%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 1009318). This variant has not been reported in the literature in individuals affected with ARL3-related conditions. This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 158 of the ARL3 protein (p.Cys158Gly). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
31
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.65
D
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
0.73
D
MutationAssessor
Pathogenic
3.4
M
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-12
D
REVEL
Pathogenic
0.79
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.96
MutPred
0.83
Gain of disorder (P = 0.0092);
MVP
0.84
MPC
1.7
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.91
gMVP
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs778332463; hg19: chr10-104445602; API