rs143319805

Variant names:

• chr3-193643378-A-G
• rs143319805
• NM_130837.3:c.1311A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP5 BP4 BS1_Supporting BS2

The NM_130837.3(OPA1):​c.1311A>G​(p.Ile437Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000867 in 1,607,894 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I437L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (3 hom.)
• Consequence: OPA1 NM_130837.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:11
• Conservation: PhyloP100: 0.888
• Publications: 42 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: Likely_benign. The variant received -5 ACMG points.

• PP5: Variant 3-193643378-A-G is Pathogenic according to our data. Variant chr3-193643378-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 50866.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37358683). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000558 (85/152300) while in subpopulation AMR AF = 0.00131 (20/15302). AF 95% confidence interval is 0.000865. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 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.1311A>G	p.Ile437Met	missense	Exon 14 of 31	NP_570850.2
	OPA1	NM_130836.3		c.1257A>G	p.Ile419Met	missense	Exon 13 of 30	NP_570849.2
	OPA1	NM_130835.3		c.1203A>G	p.Ile401Met	missense	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.1311A>G	p.Ile437Met	missense	Exon 14 of 31	ENSP00000355324.2
	OPA1	ENST00000361908.8	TSL:1	c.1257A>G	p.Ile419Met	missense	Exon 13 of 30	ENSP00000354681.3
	OPA1	ENST00000968586.1		c.1326A>G	p.Ile442Met	missense	Exon 15 of 32	ENSP00000638645.1

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000622 AC: 156 AN: 250874 AF XY: 0.000715

Gnomad AFR exome AF: 0.000249

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000785

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000899 AC: 1309 AN: 1455594 Hom.: 3 Cov.: 30 AF XY: 0.000876 AC XY: 635 AN XY: 724588

African (AFR) AF: 0.000150 AC: 5 AN: 33348

American (AMR) AF: 0.000805 AC: 36 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86100

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53404

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5748

European-Non Finnish (NFE) AF: 0.00102 AC: 1132 AN: 1106406

Other (OTH) AF: 0.000715 AC: 43 AN: 60178

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000550 AC XY: 41 AN XY: 74484

African (AFR) AF: 0.000168 AC: 7 AN: 41574

American (AMR) AF: 0.00131 AC: 20 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000630 Hom.: 0

Bravo AF: 0.000574

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000601 AC: 73

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000818

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	1	-	Abortive cerebellar ataxia (6)
2	3	-	not provided (5)
1	2	-	Autosomal dominant optic atrophy classic form (3)
1	1	-	OPA1-related disorder (2)
-	1	-	Abortive cerebellar ataxia;C0338508:Autosomal dominant optic atrophy classic form;C3276549:Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (1)
1	-	-	Abortive cerebellar ataxia;C0338508:Autosomal dominant optic atrophy classic form;C3276549:Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy;C4225163:Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) (1)
1	-	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	1	-	Optic atrophy (1)
-	1	-	Optic nerve hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.53
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.37	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		0.89
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.97
MPC		1.5
ClinPred		0.17	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.74
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143319805; hg19: chr3-193361167;