chr3-193647083-A-G

Variant names:

• chr3-193647083-A-G
• rs78767626
• NM_130837.3:c.1773A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_130837.3(OPA1):​c.1773A>G​(p.Ala591Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A591A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: OPA1 NM_130837.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0670
• Publications: 0 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

ENSG00000306963 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).

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.1773A>G	p.Ala591Ala	synonymous	Exon 19 of 31	NP_570850.2	O60313-10
	OPA1	NM_130836.3		c.1719A>G	p.Ala573Ala	synonymous	Exon 18 of 30	NP_570849.2	O60313-2
	OPA1	NM_130835.3		c.1665A>G	p.Ala555Ala	synonymous	Exon 18 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.1773A>G	p.Ala591Ala	synonymous	Exon 19 of 31	ENSP00000355324.2	O60313-10
	OPA1	ENST00000361908.8	TSL:1	c.1719A>G	p.Ala573Ala	synonymous	Exon 18 of 30	ENSP00000354681.3	O60313-2
	OPA1	ENST00000968586.1		c.1788A>G	p.Ala596Ala	synonymous	Exon 20 of 32	ENSP00000638645.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459552 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726218

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110900

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.63
PhyloP100		0.067
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs78767626; hg19: chr3-193364872;