rs75414918

Positions:

• chr3-193614733-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_130837.3(OPA1):​c.43C>A​(p.Gln15Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,612,714 control chromosomes in the GnomAD database, including 85 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (82 hom.)
• Consequence: OPA1 NM_130837.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.42

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065462887).
• BP6: Variant 3-193614733-C-A is Benign according to our data. Variant chr3-193614733-C-A is described in ClinVar as [Benign]. Clinvar id is 95726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193614733-C-A is described in Lovd as [Likely_benign]. Variant chr3-193614733-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00307 (467/152260) while in subpopulation SAS AF= 0.0168 (81/4820). AF 95% confidence interval is 0.0139. There are 3 homozygotes in gnomad4. There are 255 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPA1	NM_130837.3	c.43C>A	p.Gln15Lys	missense_variant	2/31	ENST00000361510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA1	ENST00000361510.8	c.43C>A	p.Gln15Lys	missense_variant	2/31	5	NM_130837.3	A1

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 469 AN: 152142 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00645 AC: 1605 AN: 248890 Hom.: 23 AF XY: 0.00783 AC XY: 1055 AN XY: 134730

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.0176

Gnomad SAS exome AF: 0.0238

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00307

Gnomad OTH exome AF: 0.00540

GnomAD4 exome AF: 0.00426 AC: 6215 AN: 1460454 Hom.: 82 Cov.: 32 AF XY: 0.00506 AC XY: 3680 AN XY: 726652

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00670

Gnomad4 EAS exome AF: 0.0236

Gnomad4 SAS exome AF: 0.0238

Gnomad4 FIN exome AF: 0.00168

Gnomad4 NFE exome AF: 0.00218

Gnomad4 OTH exome AF: 0.00499

GnomAD4 genome AF: 0.00307 AC: 467 AN: 152260 Hom.: 3 Cov.: 33 AF XY: 0.00343 AC XY: 255 AN XY: 74452

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.0162

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00254

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00397 Hom.: 6

Bravo AF: 0.00320

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00675 AC: 819

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00492

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 06, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2014	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Autosomal dominant optic atrophy classic form Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Abortive cerebellar ataxia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.0065	T;.;.;T;T;.;T;.;.;.
Eigen	Benign	-0.050
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D;D;D;D;.;D;D;D;D;D
MetaRNN	Benign	0.0065	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationTaster	Benign	0.89	N;N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.17	N;N;N;N;N;N;N;.;N;.
REVEL	Benign	0.22
Sift	Benign	0.30	T;T;T;T;T;T;T;.;T;.
Sift4G	Benign	0.35	T;T;T;T;T;T;T;.;T;.
Polyphen		0.0	B;.;.;B;B;.;.;.;.;.
Vest4		0.49
MVP		0.74
MPC		0.12
ClinPred		0.0053	T
GERP RS		5.1
Varity_R		0.34
gMVP		0.40

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

Other links and lift over

dbSNP: rs75414918; hg19: chr3-193332522; COSMIC: COSV100655176; COSMIC: COSV100655176;