rs863224140

Positions:

• chr3-193614797-TTTCACGAAGCATTTATCA-T
• chr3-193614797-TTTCACGAAGCATTTATCA-TTTCACGAAGCATTTATCATTCACGAAGCATTTATCA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_130837.3(OPA1):​c.113_130del​(p.Arg38_Ser43del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00222 in 1,613,980 control chromosomes in the GnomAD database, including 10 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (10 hom.)
• Consequence: OPA1 NM_130837.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: 7.07

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 Likely_benign. Variant got -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_130837.3.
• BS2: High Homozygotes in GnomAdExome4 at 10 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPA1	NM_130837.3	c.113_130del	p.Arg38_Ser43del	inframe_deletion	2/31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.113_130del	p.Arg38_Ser43del	inframe_deletion	2/31	5	NM_130837.3	ENSP00000355324	A1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00174 AC: 432 AN: 248960 Hom.: 3 AF XY: 0.00169 AC XY: 228 AN XY: 134772

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00303

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00231 AC: 3372 AN: 1461644 Hom.: 10 AF XY: 0.00220 AC XY: 1597 AN XY: 727138

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00188

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00397

Gnomad4 NFE exome AF: 0.00271

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74486

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.00210

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000672 Hom.: 1

Bravo AF: 0.00121

EpiCase AF: 0.00218

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 04, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 12, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	OPA1: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2021	This variant is associated with the following publications: (PMID: 22857269, 19303950, 12036970, 11810270, 27890673, 31521625, 20157015, 32420686, 31500643) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 05, 2023	Variant summary: OPA1 c.113_130del18 (p.Arg38_Ser43del) results in an in-frame deletion that is predicted to remove 6 amino acids from the encoded protein. The variant allele was found at a frequency of 0.0022 in 1613980 control chromosomes in the gnomAD database, including 10 homozygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance, although are not suggestive of a variant associated with highly penetrant autosomal dominant or recessive disease. c.113_130del18 has been reported in the literature in individuals affected with OPA1-Related Disorders (e.g., Thiselton_2002, Milone_2009, Barboni_2013, vandeWarrenburg_2016, Tingaud-Sequeira_2017, Heighton_2019, Marcos_2020, Rots_2023), although the variant was also found in healthy homozygous and heterozygous controls (e.g., vandeWarrenburg_2016) and found not to segregate with disease in several families (e.g., Tingaud-Sequeira_2017, Marcos_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12036970, 19303950, 23388408, 27165006, 27890673, 31521625, 32420686, 37196654). Nine submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (benign/likely benign, n = 3; VUS, n = 6). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 17, 2017	- -

Abortive cerebellar ataxia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM4. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Apr 25, 2017

This variant has been identified at an allele frequency of 0.22% in both ExAC overall and in European Americans in ESP; three homozygous individuals have been identified in these databases combined. However, this condition exhibits marked variable expressivity and incomplete penetrance, and compound heterozygous individuals have been reported with milder pathogenic variants. A previously reported patient (Milone, 2009) had a similar presentation to the patient observed in our clinic, but family segregation studies were not done in that case. The patient tested in our clinic presented with fatigue, ataxia, muscle weakness, peripheral neuropathy, ptosis, and external ophthalmoplegia. She did not have optic atrophy at age 51. Her mother had a similar clinical presentation and was deceased. The patient is also an FMR1 premutation carrier. This OPA1 variant was inherited from her father, who at age 74, had no clinical symptoms of neurological or mitochondrial dysfunction, although he had a history of migraines. -

Ptosis;C0151786:Muscle weakness;C0241005:Elevated circulating creatine kinase concentration;C0476403:EMG abnormality;C0813217:Hypomimic face;C1836156:Progressive proximal muscle weakness;C2711227:Hepatic steatosis;C4021726:EMG: myopathic abnormalities;C4025576:EMG: myotonic runs Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 06, 2015

- -

OPA1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863224140; hg19: chr3-193332586;