rs1376153949

Variant summary

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

The NM_001017989.3(OPA3):​c.385T>G​(p.Leu129Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,116 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.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

OPA3
NM_001017989.3 missense

Scores

2
9
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.27
Variant links:
Genes affected
OPA3 (HGNC:8142): (outer mitochondrial membrane lipid metabolism regulator OPA3) The mouse ortholog of this protein co-purifies with the mitochondrial inner membrane. Mutations in this gene have been shown to result in 3-methylglutaconic aciduria type III and autosomal dominant optic atrophy and cataract. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a chain Optic atrophy 3 protein (size 177) in uniprot entity OPA3_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001017989.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OPA3NM_001017989.3 linkc.385T>G p.Leu129Val missense_variant Exon 2 of 2 NP_001017989.2 Q9H6K4-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OPA3ENST00000323060.4 linkc.385T>G p.Leu129Val missense_variant Exon 2 of 2 1 ENSP00000319817.3 Q9H6K4-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460116
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726478
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.048
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
20
DANN
Uncertain
0.99
Eigen
Benign
-0.11
Eigen_PC
Benign
-0.23
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.65
T
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Uncertain
0.16
D
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-2.5
D
REVEL
Uncertain
0.40
Sift
Uncertain
0.0040
D
Sift4G
Uncertain
0.0060
D
Polyphen
0.99
D
Vest4
0.40
MutPred
0.83
Gain of MoRF binding (P = 0.0899);
MVP
0.66
MPC
1.2
ClinPred
0.95
D
GERP RS
2.6
gMVP
0.62

Splicing

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: chr19-46032472; API