3-193637285-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_130837.3(OPA1):c.1035+4T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.847 in 1,591,702 control chromosomes in the GnomAD database, including 573,156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.88 ( 59465 hom., cov: 29)

Exomes 𝑓: 0.84 ( 513691 hom. )

Consequence

OPA1
NM_130837.3 splice_donor_region, intron

Scores

Splicing: ADA: 0.00002301

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.63

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 3-193637285-T-C is Benign according to our data. Variant chr3-193637285-T-C is described in ClinVar as [Benign]. Clinvar id is 95731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193637285-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPA1	NM_130837.3 linkuse as main transcript	c.1035+4T>C		splice_donor_region_variant, intron_variant		ENST00000361510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA1	ENST00000361510.8 linkuse as main transcript	c.1035+4T>C		splice_donor_region_variant, intron_variant		5	NM_130837.3	A1	O60313-10

Frequencies

GnomAD3 genomes

AF:

0.883

AC:

133851

AN:

151590

Hom.:

59406

Cov.:

show subpopulations

Gnomad AFR

AF:

0.968

Gnomad AMI

AF:

0.890

Gnomad AMR

AF:

0.885

Gnomad ASJ

AF:

0.841

Gnomad EAS

AF:

0.960

Gnomad SAS

AF:

0.893

Gnomad FIN

AF:

0.870

Gnomad MID

AF:

0.839

Gnomad NFE

AF:

0.828

Gnomad OTH

AF:

0.877

GnomAD3 exomes

AF:

0.870

AC:

217513

AN:

249986

Hom.:

94982

AF XY:

0.868

AC XY:

117156

AN XY:

135028

show subpopulations

Gnomad AFR exome

AF:

0.971

Gnomad AMR exome

AF:

0.894

Gnomad ASJ exome

AF:

0.847

Gnomad EAS exome

AF:

0.958

Gnomad SAS exome

AF:

0.896

Gnomad FIN exome

AF:

0.875

Gnomad NFE exome

AF:

0.829

Gnomad OTH exome

AF:

0.860

GnomAD4 exome

AF:

0.844

AC:

1214822

AN:

1439994

Hom.:

513691

Cov.:

AF XY:

0.845

AC XY:

606092

AN XY:

717488

show subpopulations

Gnomad4 AFR exome

AF:

0.973

Gnomad4 AMR exome

AF:

0.895

Gnomad4 ASJ exome

AF:

0.845

Gnomad4 EAS exome

AF:

0.973

Gnomad4 SAS exome

AF:

0.899

Gnomad4 FIN exome

AF:

0.874

Gnomad4 NFE exome

AF:

0.826

Gnomad4 OTH exome

AF:

0.859

GnomAD4 genome

AF:

0.883

AC:

133970

AN:

151708

Hom.:

59465

Cov.:

AF XY:

0.885

AC XY:

65543

AN XY:

74090

show subpopulations

Gnomad4 AFR

AF:

0.969

Gnomad4 AMR

AF:

0.885

Gnomad4 ASJ

AF:

0.841

Gnomad4 EAS

AF:

0.960

Gnomad4 SAS

AF:

0.893

Gnomad4 FIN

AF:

0.870

Gnomad4 NFE

AF:

0.828

Gnomad4 OTH

AF:

0.878

Alfa

AF:

0.852

Hom.:

23520

Bravo

AF:

0.889

Asia WGS

AF:

0.923

AC:

3188

AN:

3458

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2012	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:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Autosomal dominant optic atrophy classic form

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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

BayesDel_noAF

Benign

-0.76

Cadd

Benign

Dann

Benign

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000023

dbscSNV1_RF

Benign

0.0020

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.

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