rs200983556

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_130837.3(OPA1):c.344C>T(p.Ala115Val) variant causes a missense change. The variant allele was found at a frequency of 0.000177 in 1,612,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

OPA1
NM_130837.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 5.17

Variant links:

Genes affected

OPA1 (HGNC:8140): (OPA1 mitochondrial dynamin like GTPase) The protein encoded by this gene is a nuclear-encoded mitochondrial protein with similarity to dynamin-related GTPases. The encoded protein localizes to the inner mitochondrial membrane and helps regulate mitochondrial stability and energy output. This protein also sequesters cytochrome c. Mutations in this gene have been associated with optic atrophy type 1, which is a dominantly inherited optic neuropathy resulting in progressive loss of visual acuity, leading in many cases to legal blindness. [provided by RefSeq, Aug 2017]

OPA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21705955).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000183 (267/1460344) while in subpopulation SAS AF= 0.000417 (36/86236). AF 95% confidence interval is 0.00031. There are 0 homozygotes in gnomad4_exome. There are 139 alleles in male gnomad4_exome subpopulation. Median coverage is 32. 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
OPA1	NM_130837.3 link	c.344C>T	p.Ala115Val	missense_variant	Exon 2 of 31	ENST00000361510.8	NP_570850.2	O60313-10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8 link	c.344C>T	p.Ala115Val	missense_variant	Exon 2 of 31	5	NM_130837.3	ENSP00000355324.2		O60313-10

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000221

AC:

AN:

248414

Hom.:

AF XY:

0.000252

AC XY:

AN XY:

134688

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000252

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000183

AC:

267

AN:

1460344

Hom.:

Cov.:

AF XY:

0.000191

AC XY:

139

AN XY:

726646

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000417

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000193

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000118

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000195

Hom.:

Bravo

AF:

0.000166

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in unrelated patients with optic atrophy and ataxia, and in a patient with retinitis pigmentosa, in published literature, but familial segregation information was not provided (PMID: 20157015, 25564500, 28981474); This variant is associated with the following publications: (PMID: 28981474, 25564500, 33841295, 39072298, 20157015) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2025	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 09, 2024	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 10, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 28, 2022	Variant summary: OPA1 c.344C>T (p.Ala115Val) results in a non-conservative amino acid change located in the Basic domain (Charif_2021) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 248414 control chromosomes. This frequency does not allow conclusions about variant significance although at-least one study reporting a VUS classification for this variant has commented on this frequency as being "probably too common despite literature" (example, Comander_2017). c.344C>T has been reported in the literature among cohorts of individuals with features of OPA1-related disorders ranging from optic atrophy, deafness, pericentral retinitis pigmentosa (RP)/inherited optic neuropathy, ataxia, and unspecified neuropathy (example, Santarelli_2015, Yu-Wai-Man_2010, Gaier_2017, Comander_2017, Charif_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing;provider interpretation

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Jun 12, 2017

This variant was identified in a 10 year old male with autism spectrum disorder, intellectual disability, and dietary selectivity. This variant was maternally inherited and there is no family history of optic atrophy or neurological or mitochondrial dysfunction. Clinical correlation with OPA-related disorders was thought to be poor. The variant is present in the gnomAD South Asian population at 0.068%. Computational prediction models are inconsistent. It has been reported previously in a 5 year old female with optic atrophy, deafness, ataxia, and mild myopathic changes though parental testing was not reported (Santarelli, 2015), and in a 12 year old female with optic atrophy, atixia, and neuropathy (Yu-Wai-Man, 2010). A second, paternally-inherited in-frame deletion, classified as a variant of uncertain signficance, was also identified in the OPA1 gene. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.013

T;.;.;T;T;.;T;.;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.86

D;D;D;D;.;D;D;D;D;D

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.22

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

2.0

.;M;M;M;M;M;.;M;M;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.22

N;N;N;N;N;N;N;.;N;.

REVEL

Uncertain

0.61

Sift

Benign

0.80

T;T;T;T;T;T;T;.;T;.

Sift4G

Benign

0.90

T;T;T;T;T;T;D;.;D;.

Polyphen

1.0

D;.;.;D;D;.;.;.;.;.

Vest4

0.71

MVP

0.92

MPC

0.10

ClinPred

0.035

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over