rs879255511

Positions:

• chr3-193643607-CCAT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_130837.3(OPA1):​c.1461_1463del​(p.Ile488del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OPA1 NM_130837.3 inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.26

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 7) in uniprot entity OPA1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_130837.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_130837.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-193643607-CCAT-C is Pathogenic according to our data. Variant chr3-193643607-CCAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 5086.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-193643607-CCAT-C is described in Lovd as [Pathogenic]. Variant chr3-193643607-CCAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPA1	NM_130837.3	c.1461_1463del	p.Ile488del	inframe_deletion	15/31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.1461_1463del	p.Ile488del	inframe_deletion	15/31	5	NM_130837.3	ENSP00000355324	A1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant optic atrophy classic form Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs879255511; hg19: chr3-193361396;