rs34307082

Variant names:

• chr3-193618887-C-T
• rs34307082
• NM_130837.3:c.629C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_130837.3(OPA1):​c.629C>T​(p.Ala210Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,612,898 control chromosomes in the GnomAD database, including 696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A210A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (49 hom., cov: 33)
  • Exomes 𝑓: 0.027 (647 hom.)
• Consequence: OPA1 NM_130837.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.13
• Publications: 21 publications found

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-AS1 (HGNC:40421): (OPA1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071130693).
• BP6: Variant 3-193618887-C-T is Benign according to our data. Variant chr3-193618887-C-T is described in ClinVar as Benign. ClinVar VariationId is 95729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0237 (3613/152146) while in subpopulation NFE AF = 0.0298 (2024/68008). AF 95% confidence interval is 0.0287. There are 49 homozygotes in GnomAd4. There are 1731 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA1	NM_130837.3	c.629C>T	p.Ala210Val	missense_variant	Exon 6 of 31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.629C>T	p.Ala210Val	missense_variant	Exon 6 of 31	5	NM_130837.3	ENSP00000355324.2

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3611 AN: 152028 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.0295

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0287

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0227 AC: 5716 AN: 251380 AF XY: 0.0233

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.0252

Gnomad FIN exome AF: 0.0299

Gnomad NFE exome AF: 0.0267

Gnomad OTH exome AF: 0.0217

GnomAD4 exome AF: 0.0272 AC: 39755 AN: 1460752 Hom.: 647 Cov.: 31 AF XY: 0.0271 AC XY: 19659 AN XY: 726744

African (AFR) AF: 0.0149 AC: 497 AN: 33462

American (AMR) AF: 0.0116 AC: 519 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0367 AC: 958 AN: 26130

East Asian (EAS) AF: 0.0256 AC: 1017 AN: 39672

South Asian (SAS) AF: 0.0163 AC: 1402 AN: 86250

European-Finnish (FIN) AF: 0.0266 AC: 1422 AN: 53398

Middle Eastern (MID) AF: 0.0156 AC: 90 AN: 5766

European-Non Finnish (NFE) AF: 0.0290 AC: 32190 AN: 1110998

Other (OTH) AF: 0.0275 AC: 1660 AN: 60356

GnomAD4 genome AF: 0.0237 AC: 3613 AN: 152146 Hom.: 49 Cov.: 33 AF XY: 0.0233 AC XY: 1731 AN XY: 74376

African (AFR) AF: 0.0149 AC: 619 AN: 41514

American (AMR) AF: 0.0162 AC: 248 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 115 AN: 3472

East Asian (EAS) AF: 0.0296 AC: 153 AN: 5172

South Asian (SAS) AF: 0.0145 AC: 70 AN: 4814

European-Finnish (FIN) AF: 0.0287 AC: 303 AN: 10570

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0298 AC: 2024 AN: 68008

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0267 Hom.: 207

Bravo AF: 0.0217

TwinsUK AF: 0.0316 AC: 117

ALSPAC AF: 0.0270 AC: 104

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.0288 AC: 248

ExAC AF: 0.0216 AC: 2626

Asia WGS AF: 0.0250 AC: 85 AN: 3478

EpiCase AF: 0.0260

EpiControl AF: 0.0206

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Apr 06, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal dominant optic atrophy classic form Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T;.;.;T;T;.;.;.;.;.;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D;D;D;.;D;D;D;D;D;D;D
MetaRNN	Benign	0.0071	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.1	.;.;.;M;M;M;.;.;.;.;.;.
PhyloP100		3.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.69	N;N;N;.;N;N;.;.;.;.;D;.
REVEL	Uncertain	0.38
Sift	Benign	0.17	T;T;T;.;T;D;.;.;.;.;D;.
Sift4G	Benign	0.29	T;T;T;.;T;T;.;.;.;.;D;.
Polyphen		0.91	P;.;.;P;P;.;.;.;.;.;.;.
Vest4		0.31
MPC		0.096
ClinPred		0.018	T
GERP RS		5.5
Varity_R		0.072
gMVP		0.47
Mutation Taster		=65/35	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34307082; hg19: chr3-193336676; COSMIC: COSV104418915;