chr10-102685865-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_004311.4(ARL3):​c.452G>T​(p.Arg151Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R151Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ARL3
NM_004311.4 missense

Scores

12
6
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.17
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 6 ACMG points.

PM1
In a chain ADP-ribosylation factor-like protein 3 (size 180) in uniprot entity ARL3_HUMAN there are 12 pathogenic changes around while only 3 benign (80%) in NM_004311.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARL3NM_004311.4 linkc.452G>T p.Arg151Leu missense_variant Exon 5 of 6 ENST00000260746.6 NP_004302.1 P36405
ARL3XM_017016260.2 linkc.452G>T p.Arg151Leu missense_variant Exon 5 of 6 XP_016871749.1 P36405

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARL3ENST00000260746.6 linkc.452G>T p.Arg151Leu missense_variant Exon 5 of 6 1 NM_004311.4 ENSP00000260746.4 P36405

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461758
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.64
D
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.35
D
MetaRNN
Pathogenic
0.93
D
MetaSVM
Uncertain
0.61
D
MutationAssessor
Pathogenic
3.1
M
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-6.8
D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.016
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.83
MutPred
0.73
Loss of solvent accessibility (P = 0.0013);
MVP
0.74
MPC
1.7
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.70
gMVP
0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-104445622; API