rs780492515

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025136.4(OPA3):c.487C>T(p.Leu163Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L163L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

OPA3
NM_025136.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.599

Publications

1 publications found

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]

OPA3 Gene-Disease associations (from GenCC):

optic atrophy 3
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
3-methylglutaconic aciduria type 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae)

OPA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18698195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA3	NM_025136.4 link	c.487C>T	p.Leu163Phe	missense_variant	Exon 2 of 2	ENST00000263275.5	NP_079412.1	Q9H6K4-1
OPA3	XM_006723403.5 link	c.328C>T	p.Leu110Phe	missense_variant	Exon 3 of 3		XP_006723466.1	B4DK77
OPA3	NM_001017989.3 link	c.143-24111C>T		intron_variant	Intron 1 of 1		NP_001017989.2	Q9H6K4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OPA3	ENST00000263275.5 link	c.487C>T	p.Leu163Phe	missense_variant	Exon 2 of 2	1	NM_025136.4	ENSP00000263275.4	Q9H6K4-1
OPA3	ENST00000323060.4 link	c.143-24111C>T		intron_variant	Intron 1 of 1	1		ENSP00000319817.3	Q9H6K4-2
OPA3	ENST00000544371.1 link	c.328C>T	p.Leu110Phe	missense_variant	Exon 2 of 2	2		ENSP00000442839.1	B4DK77

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000814

AC:

AN:

245650

AF XY:

0.00000745

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

AN:

1460802

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726812

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111964

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

3-Methylglutaconic aciduria type 3;C1833809:Optic atrophy 3

Uncertain:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 163 of the OPA3 protein (p.Leu163Phe). This variant is present in population databases (rs780492515, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with OPA3-related conditions. ClinVar contains an entry for this variant (Variation ID: 556177). 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. 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. -

3-Methylglutaconic aciduria type 3

Uncertain:1

Jan 16, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.59

T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

2.0

M;.

PhyloP100

0.60

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.23

Sift

Benign

0.10

T;T

Sift4G

Benign

0.11

T;D

Polyphen

0.88

P;.

Vest4

0.11

MutPred

0.25

Loss of MoRF binding (P = 0.1045);.;

MVP

0.71

ClinPred

0.38

GERP RS

1.2

Varity_R

0.056

Mutation Taster

=33/67

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over