NM_130837.3:c.653C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_130837.3(OPA1):c.653C>T(p.Ser218Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,613,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

OPA1
NM_130837.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 3.21

Publications

6 publications found

Variant links:

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 links:

OPA1-AS1 (HGNC:40421): (OPA1 antisense RNA 1)

OPA1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10418704).

BP6

Variant 3-193618911-C-T is Benign according to our data. Variant chr3-193618911-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 344482.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000285 (417/1461494) while in subpopulation NFE AF = 0.000341 (379/1111680). AF 95% confidence interval is 0.000312. There are 0 homozygotes in GnomAdExome4. There are 210 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OPA1	NM_130837.3	MANE Select	c.653C>T	p.Ser218Phe	missense	Exon 6 of 31	NP_570850.2
OPA1	NM_130836.3		c.599C>T	p.Ser200Phe	missense	Exon 5 of 30	NP_570849.2
OPA1	NM_130835.3		c.545C>T	p.Ser182Phe	missense	Exon 5 of 30	NP_570848.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OPA1	ENST00000361510.8	TSL:5 MANE Select	c.653C>T	p.Ser218Phe	missense	Exon 6 of 31	ENSP00000355324.2
OPA1	ENST00000361908.8	TSL:1	c.599C>T	p.Ser200Phe	missense	Exon 5 of 30	ENSP00000354681.3
OPA1	ENST00000968586.1		c.653C>T	p.Ser218Phe	missense	Exon 6 of 32	ENSP00000638645.1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000994

AC:

AN:

251406

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000285

AC:

417

AN:

1461494

Hom.:

Cov.:

AF XY:

0.000289

AC XY:

210

AN XY:

727070

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000341

AC:

379

AN:

1111680

Other (OTH)

AF:

0.000580

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000151

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000252

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Abortive cerebellar ataxia;C0338508:Autosomal dominant optic atrophy classic form;C1847730:Glaucoma, normal tension, susceptibility to;C3276549:Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy;C4225163:Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) (1)

Autosomal dominant optic atrophy classic form (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.0089

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.32

MutationAssessor

Benign

0.74

PhyloP100

3.2

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.050

REVEL

Uncertain

0.34

Sift

Uncertain

0.027

Sift4G

Benign

0.25

Polyphen

0.11

Vest4

0.54

MVP

0.54

MPC

0.11

ClinPred

0.039

GERP RS

4.8

Varity_R

0.079

gMVP

0.30

Mutation Taster

=79/21

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over