chr3-193647083-A-C

Variant names:

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

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.1773A>C​(p.Ala591Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,611,292 control chromosomes in the GnomAD database, including 780 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (70 hom., cov: 32)
  • Exomes 𝑓: 0.029 (710 hom.)
• Consequence: OPA1 NM_130837.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0670
• Publications: 10 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 3-193647083-A-C is Benign according to our data. Variant chr3-193647083-A-C is described in ClinVar as Benign. ClinVar VariationId is 95711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.067 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0312 (4754/152260) while in subpopulation AFR AF = 0.0393 (1633/41532). AF 95% confidence interval is 0.0377. There are 70 homozygotes in GnomAd4. There are 2296 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 70 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	NM_130837.3	MANE Select	c.1773A>C	p.Ala591Ala	synonymous	Exon 19 of 31	NP_570850.2	O60313-10
	OPA1	NM_130836.3		c.1719A>C	p.Ala573Ala	synonymous	Exon 18 of 30	NP_570849.2	O60313-2
	OPA1	NM_130835.3		c.1665A>C	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>C	p.Ala591Ala	synonymous	Exon 19 of 31	ENSP00000355324.2	O60313-10
	OPA1	ENST00000361908.8	TSL:1	c.1719A>C	p.Ala573Ala	synonymous	Exon 18 of 30	ENSP00000354681.3	O60313-2
	OPA1	ENST00000968586.1		c.1788A>C	p.Ala596Ala	synonymous	Exon 20 of 32	ENSP00000638645.1

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4741 AN: 152142 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.0293

Gnomad SAS AF: 0.0252

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0299

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0256 AC: 6400 AN: 249756 AF XY: 0.0262

Gnomad AFR exome AF: 0.0380

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0367

Gnomad EAS exome AF: 0.0252

Gnomad FIN exome AF: 0.0294

Gnomad NFE exome AF: 0.0268

Gnomad OTH exome AF: 0.0231

GnomAD4 exome AF: 0.0286 AC: 41727 AN: 1459032 Hom.: 710 Cov.: 30 AF XY: 0.0287 AC XY: 20830 AN XY: 725988

African (AFR) AF: 0.0393 AC: 1313 AN: 33430

American (AMR) AF: 0.0127 AC: 568 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0365 AC: 954 AN: 26114

East Asian (EAS) AF: 0.0257 AC: 1020 AN: 39642

South Asian (SAS) AF: 0.0264 AC: 2278 AN: 86170

European-Finnish (FIN) AF: 0.0263 AC: 1377 AN: 52428

Middle Eastern (MID) AF: 0.0186 AC: 107 AN: 5764

European-Non Finnish (NFE) AF: 0.0291 AC: 32271 AN: 1110462

Other (OTH) AF: 0.0305 AC: 1839 AN: 60310

GnomAD4 genome AF: 0.0312 AC: 4754 AN: 152260 Hom.: 70 Cov.: 32 AF XY: 0.0308 AC XY: 2296 AN XY: 74440

African (AFR) AF: 0.0393 AC: 1633 AN: 41532

American (AMR) AF: 0.0182 AC: 279 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 115 AN: 3470

East Asian (EAS) AF: 0.0294 AC: 152 AN: 5178

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4828

European-Finnish (FIN) AF: 0.0285 AC: 303 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0299 AC: 2037 AN: 68024

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.0297 Hom.: 122

Bravo AF: 0.0296

Asia WGS AF: 0.0330 AC: 114 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0209

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal dominant optic atrophy classic form (1)
-	-	1	Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.60
PhyloP100		0.067
Mutation Taster		=99/1	polymorphism (auto)

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; COSMIC: COSV104418916;