chr3-193643409-A-C

Variant names:

• chr3-193643409-A-C
• rs149752576
• NM_130837.3:c.1342A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_130837.3(OPA1):​c.1342A>C​(p.Arg448Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.00415 in 1,612,042 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (83 hom.)
• Consequence: OPA1 NM_130837.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.10
• Publications: 13 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 3-193643409-A-C is Benign according to our data. Variant chr3-193643409-A-C is described in ClinVar as Benign. ClinVar VariationId is 95709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00308 (469/152350) while in subpopulation SAS AF = 0.0172 (83/4826). AF 95% confidence interval is 0.0142. There are 3 homozygotes in GnomAd4. There are 256 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1342A>C	p.Arg448Arg	synonymous	Exon 14 of 31	NP_570850.2
	OPA1	NM_130836.3		c.1288A>C	p.Arg430Arg	synonymous	Exon 13 of 30	NP_570849.2
	OPA1	NM_130835.3		c.1234A>C	p.Arg412Arg	synonymous	Exon 13 of 30	NP_570848.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	ENST00000361510.8	TSL:5 MANE Select	c.1342A>C	p.Arg448Arg	synonymous	Exon 14 of 31	ENSP00000355324.2
	OPA1	ENST00000361908.8	TSL:1	c.1288A>C	p.Arg430Arg	synonymous	Exon 13 of 30	ENSP00000354681.3
	OPA1	ENST00000968586.1		c.1357A>C	p.Arg453Arg	synonymous	Exon 15 of 32	ENSP00000638645.1

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 471 AN: 152232 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00642 AC: 1612 AN: 251112 AF XY: 0.00782

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.0176

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00307

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00427 AC: 6226 AN: 1459692 Hom.: 83 Cov.: 30 AF XY: 0.00509 AC XY: 3695 AN XY: 726336

African (AFR) AF: 0.000838 AC: 28 AN: 33432

American (AMR) AF: 0.00226 AC: 101 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 173 AN: 26110

East Asian (EAS) AF: 0.0237 AC: 939 AN: 39632

South Asian (SAS) AF: 0.0239 AC: 2057 AN: 86192

European-Finnish (FIN) AF: 0.00169 AC: 90 AN: 53410

Middle Eastern (MID) AF: 0.0184 AC: 106 AN: 5758

European-Non Finnish (NFE) AF: 0.00219 AC: 2432 AN: 1110128

Other (OTH) AF: 0.00497 AC: 300 AN: 60312

GnomAD4 genome AF: 0.00308 AC: 469 AN: 152350 Hom.: 3 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74504

African (AFR) AF: 0.000625 AC: 26 AN: 41582

American (AMR) AF: 0.00281 AC: 43 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.0162 AC: 84 AN: 5186

South Asian (SAS) AF: 0.0172 AC: 83 AN: 4826

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00254 AC: 173 AN: 68032

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00285 Hom.: 2

Bravo AF: 0.00320

Asia WGS AF: 0.0120 AC: 41 AN: 3474

EpiCase AF: 0.00463

EpiControl AF: 0.00486

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal dominant optic atrophy classic form (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.65
PhyloP100		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs149752576; hg19: chr3-193361198; COSMIC: COSV100655178; COSMIC: COSV100655178;