chr3-193692066-AAGTT-A

Variant names:

• chr3-193692066-AAGTT-A
• rs879255560
• NM_130837.3:c.2990_2993delTTAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_130837.3(OPA1):​c.2990_2993delTTAG​(p.Val997GlufsTer25) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,360,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V997V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: OPA1 NM_130837.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.30
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant optic atrophy, classic form

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• optic atrophy

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• OPA1-related optic atrophy with or without extraocular features

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Behr syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type)

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal dominant optic atrophy plus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-193692066-AAGTT-A is Pathogenic according to our data. Variant chr3-193692066-AAGTT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130837.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	NM_130837.3	MANE Select	c.2990_2993delTTAG	p.Val997GlufsTer25	frameshift	Exon 30 of 31	NP_570850.2	O60313-10
	OPA1	NM_130836.3		c.2936_2939delTTAG	p.Val979GlufsTer25	frameshift	Exon 29 of 30	NP_570849.2	O60313-2
	OPA1	NM_130835.3		c.2882_2885delTTAG	p.Val961GlufsTer25	frameshift	Exon 29 of 30	NP_570848.1	E5KLJ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	ENST00000361510.8	TSL:5 MANE Select	c.2990_2993delTTAG	p.Val997GlufsTer25	frameshift	Exon 30 of 31	ENSP00000355324.2	O60313-10
	OPA1	ENST00000361908.8	TSL:1	c.2936_2939delTTAG	p.Val979GlufsTer25	frameshift	Exon 29 of 30	ENSP00000354681.3	O60313-2
	OPA1	ENST00000495261.1	TSL:1	n.676_679delTTAG		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1360024 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 676598

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31362

American (AMR) AF: 0.00 AC: 0 AN: 40542

Ashkenazi Jewish (ASJ) AF: 0.0000400 AC: 1 AN: 25030

East Asian (EAS) AF: 0.00 AC: 0 AN: 38144

South Asian (SAS) AF: 0.00 AC: 0 AN: 80068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5024

European-Non Finnish (NFE) AF: 9.68e-7 AC: 1 AN: 1032670

Other (OTH) AF: 0.00 AC: 0 AN: 56534

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
2	-	-	Autosomal dominant optic atrophy classic form (2)
1	-	-	Optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879255560; hg19: chr3-193409855;