rs111688935

Variant names:

• chr3-193665007-C-G
• rs111688935
• NM_130837.3:c.2778+11C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_130837.3(OPA1):​c.2778+11C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00698 in 1,395,254 control chromosomes in the GnomAD database, including 591 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (338 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (253 hom.)
• Consequence: OPA1 NM_130837.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.729
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 3-193665007-C-G is Benign according to our data. Variant chr3-193665007-C-G is described in ClinVar as Benign. ClinVar VariationId is 95722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

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.2778+11C>G		intron	N/A	NP_570850.2
	OPA1	NM_130836.3		c.2724+11C>G		intron	N/A	NP_570849.2
	OPA1	NM_130835.3		c.2670+11C>G		intron	N/A	NP_570848.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	ENST00000361510.8	TSL:5 MANE Select	c.2778+11C>G		intron	N/A	ENSP00000355324.2
	OPA1	ENST00000361908.8	TSL:1	c.2724+11C>G		intron	N/A	ENSP00000354681.3
	OPA1	ENST00000361715.6	TSL:5	c.2670+11C>G		intron	N/A	ENSP00000355311.2

Frequencies

GnomAD3 genomes AF: 0.0343 AC: 5207 AN: 151606 Hom.: 337 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000952

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000251

Gnomad OTH AF: 0.0254

GnomAD2 exomes AF: 0.00895 AC: 2229 AN: 248918 AF XY: 0.00634

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.00543

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.00346

GnomAD4 exome AF: 0.00363 AC: 4519 AN: 1243530 Hom.: 253 Cov.: 18 AF XY: 0.00309 AC XY: 1948 AN XY: 629866

African (AFR) AF: 0.123 AC: 3589 AN: 29186

American (AMR) AF: 0.00534 AC: 236 AN: 44210

Ashkenazi Jewish (ASJ) AF: 0.0000405 AC: 1 AN: 24706

East Asian (EAS) AF: 0.00 AC: 0 AN: 38472

South Asian (SAS) AF: 0.000838 AC: 68 AN: 81194

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53174

Middle Eastern (MID) AF: 0.00770 AC: 41 AN: 5326

European-Non Finnish (NFE) AF: 0.000113 AC: 103 AN: 914174

Other (OTH) AF: 0.00889 AC: 472 AN: 53088

GnomAD4 genome AF: 0.0344 AC: 5223 AN: 151724 Hom.: 338 Cov.: 33 AF XY: 0.0323 AC XY: 2392 AN XY: 74130

African (AFR) AF: 0.120 AC: 4984 AN: 41384

American (AMR) AF: 0.0106 AC: 162 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4812

European-Finnish (FIN) AF: 0.0000952 AC: 1 AN: 10504

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000251 AC: 17 AN: 67834

Other (OTH) AF: 0.0252 AC: 53 AN: 2106

Alfa AF: 0.0180 Hom.: 27

Bravo AF: 0.0386

Asia WGS AF: 0.00926 AC: 32 AN: 3470

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	-0.66
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		-0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs111688935; hg19: chr3-193382796; COSMIC: COSV104418891;