rs73069703

Variant names:

• chr3-193654898-A-G
• rs73069703
• NM_130837.3:c.2049A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_130837.3(OPA1):​c.2049A>G​(p.Val683Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,613,918 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (34 hom.)
• Consequence: OPA1 NM_130837.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.280
• Publications: 7 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 3-193654898-A-G is Benign according to our data. Variant chr3-193654898-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00737 (1122/152314) while in subpopulation AFR AF = 0.0218 (907/41578). AF 95% confidence interval is 0.0206. There are 10 homozygotes in GnomAd4. There are 541 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR,SD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	NM_130837.3	MANE Select	c.2049A>G	p.Val683Val	synonymous	Exon 22 of 31	NP_570850.2
	OPA1	NM_130836.3		c.1995A>G	p.Val665Val	synonymous	Exon 21 of 30	NP_570849.2
	OPA1	NM_130835.3		c.1941A>G	p.Val647Val	synonymous	Exon 21 of 30	NP_570848.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	ENST00000361510.8	TSL:5 MANE Select	c.2049A>G	p.Val683Val	synonymous	Exon 22 of 31	ENSP00000355324.2
	OPA1	ENST00000361908.8	TSL:1	c.1995A>G	p.Val665Val	synonymous	Exon 21 of 30	ENSP00000354681.3
	OPA1	ENST00000361715.6	TSL:5	c.1941A>G	p.Val647Val	synonymous	Exon 21 of 30	ENSP00000355311.2

Frequencies

GnomAD3 genomes AF: 0.00736 AC: 1120 AN: 152196 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00445 AC: 1116 AN: 250932 AF XY: 0.00408

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0204

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00202 AC: 2959 AN: 1461604 Hom.: 34 Cov.: 31 AF XY: 0.00217 AC XY: 1578 AN XY: 727098

African (AFR) AF: 0.0210 AC: 701 AN: 33460

American (AMR) AF: 0.00315 AC: 141 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00345 AC: 90 AN: 26124

East Asian (EAS) AF: 0.0223 AC: 885 AN: 39634

South Asian (SAS) AF: 0.00867 AC: 748 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5760

European-Non Finnish (NFE) AF: 0.000121 AC: 135 AN: 1111898

Other (OTH) AF: 0.00409 AC: 247 AN: 60376

GnomAD4 genome AF: 0.00737 AC: 1122 AN: 152314 Hom.: 10 Cov.: 32 AF XY: 0.00726 AC XY: 541 AN XY: 74484

African (AFR) AF: 0.0218 AC: 907 AN: 41578

American (AMR) AF: 0.00346 AC: 53 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.0185 AC: 96 AN: 5188

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68014

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00368 Hom.: 2

Bravo AF: 0.00819

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Autosomal dominant optic atrophy classic form (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.0
DANN	Benign	0.68
PhyloP100		-0.28
Mutation Taster		=98/2	polymorphism

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: rs73069703; hg19: chr3-193372687;