3-193638064-A-G

Position:

chr3-193638064-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_130837.3(OPA1):c.1148A>G(p.Lys383Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K383K) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

OPA1
NM_130837.3 missense, splice_region

Scores

Splicing: ADA: 0.9950

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 9.31

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:

OPA1 (HGNC:):

OPA1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a strand (size 6) in uniprot entity OPA1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_130837.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.826

PP5

Variant 3-193638064-A-G is Pathogenic according to our data. Variant chr3-193638064-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 95733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193638064-A-G is described in Lovd as [Pathogenic]. Variant chr3-193638064-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPA1	NM_130837.3 linkuse as main transcript	c.1148A>G	p.Lys383Arg	missense_variant, splice_region_variant	11/31	ENST00000361510.8	NP_570850.2	O60313-10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8 linkuse as main transcript	c.1148A>G	p.Lys383Arg	missense_variant, splice_region_variant	11/31	5	NM_130837.3	ENSP00000355324.2		O60313-10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458436

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725770

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 22, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 07, 2023	This variant has been identified in multiple unrelated individuals with optic atrophy. Experimental evidence suggests this variant results in abnormal RNA splicing and an in-frame deletion of 38 amino acids from the protein (PMID: 14961560). This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). The variant is located in a region that is considered important for protein function and/or structure. Computational tools predict that this variant is damaging. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2021	RT-PCR analysis demonstrates that c.983 A>G modifies the consensus splice donor site in intron 9 resulting in in-frame skipping of exon 9 (Baris et al., 2003); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 14961560, 22857269, 26385429, 25699009, 16418602, 23384603, 30581410, 16735988, 20301426, 22042570, 27535533, 25525159) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 328 of the OPA1 protein (p.Lys328Arg). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dominant optic atrophy (PMID: 14961560, 22857269). ClinVar contains an entry for this variant (Variation ID: 95733). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change results in skipping of exon 9, but is expected to preserve the integrity of the reading-frame (PMID: 14961560). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital	Dec 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type)

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

May 23, 2023

This sequence variant is a single nucleotide substitution (A>G) at position 983 of the coding sequence of the OPA1 gene that results in a lysine to arginine amino acid change at residue 328 of the OPA1 mitochondrial dymin like GTPase protein. Additiolly, this variant falls within the splice donor region for exon 9 and has been experimentally confirmed to result in exon 9 skipping (PMID: 14961560) which disrupts the dymin type G domain of OPA1. This is a previously reported variant (ClinVar 95733) that has been observed in many individuals affected by Autosomal dominant inheritance optic atrophy (PMID: 14961560, 22857269, 25699009 35146926), and segregates with disease in affected families. This variant is absent from the gnomAD population database (0/0 alleles). Multiple bioinformatic tools predict that this Lys to Arg amino acid change would be damaging, and the Lys328 residue at this position is highly conserved across the vertebrate species examined. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: BS4, PM2, PP1, PP3, PS3 -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 16, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with OPA1-related conditions (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Truncating variants and mutations in the C-terminal domain are associated with dominant optic atrophy. Individuals carrying missense variants clustered within the GTPase domain generally develop an optic atrophy syndrome. Lastly, biallelic variants have been associated with early onset Behr syndrome or Leigh syndrome, OPA1-related (MONDO#0009723) (PMID: 31500643, 28494813, 25012220, 30165240). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17306754). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant lies within the non-canonical splice region of an exon. Analysis of total RNA obtained from an affected individual demonstrated exon skipping, which will result in an in-frame deletion of 38 amino acids (NP_570850.2; p.(Val346_Lys383del)) (PMID: 14961560). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - An alternative nucleotide change at the same non-canonical splice site is present in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten families with autosomal dominant optic atrophy (MIM#165500; PMID:22857269), at least one report of optic atrophy plus syndrome (MIM#125250; PMID:29261183); and consistently classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Autosomal dominant optic atrophy classic form

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

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

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.8

.;.;.;L;L;.;.;.;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.6

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

REVEL

Pathogenic

0.83

Sift

Uncertain

0.018

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

Sift4G

Uncertain

0.033

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

Polyphen

1.0

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

Vest4

0.71

MutPred

0.51

.;.;Gain of glycosylation at S380 (P = 0.0135);.;.;.;.;.;.;.;.;

MVP

0.92

MPC

1.4

ClinPred

0.96

GERP RS

5.5

Varity_R

0.50

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.39

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.39

Position offset: 1

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