19-45529184-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_StrongBS1_Supporting

The NM_001017989.3(OPA3):​c.415C>T​(p.Gln139*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000377 in 1,458,268 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.000038 ( 1 hom. )

Consequence

OPA3
NM_001017989.3 stop_gained

Scores

3
3
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.94
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 Uncertain_significance. Variant got 3 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.236 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000377 (55/1458268) while in subpopulation SAS AF= 0.000626 (54/86222). AF 95% confidence interval is 0.000492. There are 1 homozygotes in gnomad4_exome. There are 43 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OPA3NM_001017989.3 linkc.415C>T p.Gln139* stop_gained 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.415C>T p.Gln139* stop_gained Exon 2 of 2 1 ENSP00000319817.3 Q9H6K4-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.0000957
AC:
23
AN:
240216
Hom.:
1
AF XY:
0.000137
AC XY:
18
AN XY:
131506
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000756
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000377
AC:
55
AN:
1458268
Hom.:
1
Cov.:
31
AF XY:
0.0000593
AC XY:
43
AN XY:
725646
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:
0.000626
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.000179
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000745
AC:
9

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

3-Methylglutaconic aciduria type 3 Uncertain:1
Aug 11, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.47
CADD
Pathogenic
36
DANN
Uncertain
0.99
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Pathogenic
0.97
D
Vest4
0.42
GERP RS
1.2

Splicing

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: rs762180740; hg19: chr19-46032442; API