3-193615742-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_130837.3(OPA1):​c.420G>T​(p.Val140=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00892 in 1,610,888 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 7 hom., cov: 33)
Exomes 𝑓: 0.0092 ( 88 hom. )

Consequence

OPA1
NM_130837.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.654
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.53).
BP6
Variant 3-193615742-G-T is Benign according to our data. Variant chr3-193615742-G-T is described in ClinVar as [Benign]. Clinvar id is 95725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193615742-G-T is described in Lovd as [Benign]. Variant chr3-193615742-G-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.654 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00618 (941/152268) while in subpopulation SAS AF= 0.0104 (50/4816). AF 95% confidence interval is 0.00859. There are 7 homozygotes in gnomad4. There are 451 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 7 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
OPA1NM_130837.3 linkuse as main transcriptc.420G>T p.Val140= synonymous_variant 3/31 ENST00000361510.8 NP_570850.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
OPA1ENST00000361510.8 linkuse as main transcriptc.420G>T p.Val140= synonymous_variant 3/315 NM_130837.3 ENSP00000355324 A1O60313-10

Frequencies

GnomAD3 genomes
AF:
0.00618
AC:
940
AN:
152150
Hom.:
7
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00154
Gnomad AMI
AF:
0.00768
Gnomad AMR
AF:
0.00347
Gnomad ASJ
AF:
0.0159
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0102
Gnomad FIN
AF:
0.00623
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.00919
Gnomad OTH
AF:
0.00862
GnomAD3 exomes
AF:
0.00836
AC:
2103
AN:
251424
Hom.:
19
AF XY:
0.00915
AC XY:
1243
AN XY:
135882
show subpopulations
Gnomad AFR exome
AF:
0.00178
Gnomad AMR exome
AF:
0.00411
Gnomad ASJ exome
AF:
0.0123
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0138
Gnomad FIN exome
AF:
0.00577
Gnomad NFE exome
AF:
0.0105
Gnomad OTH exome
AF:
0.0116
GnomAD4 exome
AF:
0.00921
AC:
13436
AN:
1458620
Hom.:
88
Cov.:
29
AF XY:
0.00948
AC XY:
6881
AN XY:
725850
show subpopulations
Gnomad4 AFR exome
AF:
0.00156
Gnomad4 AMR exome
AF:
0.00434
Gnomad4 ASJ exome
AF:
0.0133
Gnomad4 EAS exome
AF:
0.0000505
Gnomad4 SAS exome
AF:
0.0147
Gnomad4 FIN exome
AF:
0.00597
Gnomad4 NFE exome
AF:
0.00957
Gnomad4 OTH exome
AF:
0.00896
GnomAD4 genome
AF:
0.00618
AC:
941
AN:
152268
Hom.:
7
Cov.:
33
AF XY:
0.00606
AC XY:
451
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.00154
Gnomad4 AMR
AF:
0.00346
Gnomad4 ASJ
AF:
0.0159
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0104
Gnomad4 FIN
AF:
0.00623
Gnomad4 NFE
AF:
0.00919
Gnomad4 OTH
AF:
0.00853
Alfa
AF:
0.00760
Hom.:
3
Bravo
AF:
0.00602
Asia WGS
AF:
0.00433
AC:
15
AN:
3478
EpiCase
AF:
0.0112
EpiControl
AF:
0.0104

ClinVar

Significance: Benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:7
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024OPA1: BP4, BP7, BS1, BS2 -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 23, 2016- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsOct 29, 2018- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
not specified Benign:4
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 01, 2013- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 03, 2013This 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. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Autosomal dominant optic atrophy classic form Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
BayesDel_noAF
Benign
-0.53
CADD
Benign
4.4
DANN
Benign
0.80

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs35801538; hg19: chr3-193333531; COSMIC: COSV104418833; COSMIC: COSV104418833; API