NM_130837.3:c.2872+25T>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_130837.3(OPA1):c.2872+25T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,514,964 control chromosomes in the GnomAD database, including 141,876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 13962 hom., cov: 32)

Exomes 𝑓: 0.43 ( 127914 hom. )

Consequence

OPA1
NM_130837.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.247

Publications

12 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 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

OPA1 links:

ENSG00000306963 (HGNC:):

ENSG00000306963 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 3-193666414-T-A is Benign according to our data. Variant chr3-193666414-T-A is described in ClinVar as Benign. ClinVar VariationId is 1291406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA1	NM_130837.3 link	c.2872+25T>A		intron_variant	Intron 28 of 30	ENST00000361510.8	NP_570850.2	O60313-10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8 link	c.2872+25T>A		intron_variant	Intron 28 of 30	5	NM_130837.3	ENSP00000355324.2		O60313-10

Frequencies

GnomAD3 genomes

AF:

0.424

AC:

64400

AN:

151968

Hom.:

13953

Cov.:

show subpopulations

Gnomad AFR

AF:

0.400

Gnomad AMI

AF:

0.514

Gnomad AMR

AF:

0.409

Gnomad ASJ

AF:

0.427

Gnomad EAS

AF:

0.318

Gnomad SAS

AF:

0.373

Gnomad FIN

AF:

0.539

Gnomad MID

AF:

0.385

Gnomad NFE

AF:

0.434

Gnomad OTH

AF:

0.412

GnomAD2 exomes

AF:

0.422

AC:

105860

AN:

250798

AF XY:

0.419

show subpopulations

Gnomad AFR exome

AF:

0.404

Gnomad AMR exome

AF:

0.399

Gnomad ASJ exome

AF:

0.430

Gnomad EAS exome

AF:

0.320

Gnomad FIN exome

AF:

0.543

Gnomad NFE exome

AF:

0.436

Gnomad OTH exome

AF:

0.421

GnomAD4 exome

AF:

0.430

AC:

585894

AN:

1362878

Hom.:

127914

Cov.:

AF XY:

0.428

AC XY:

292298

AN XY:

683642

show subpopulations

African (AFR)

AF:

0.410

AC:

12940

AN:

31528

American (AMR)

AF:

0.400

AC:

17806

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.436

AC:

11110

AN:

25500

East Asian (EAS)

AF:

0.260

AC:

10205

AN:

39208

South Asian (SAS)

AF:

0.378

AC:

31882

AN:

84298

European-Finnish (FIN)

AF:

0.541

AC:

28862

AN:

53314

Middle Eastern (MID)

AF:

0.369

AC:

2054

AN:

5566

European-Non Finnish (NFE)

AF:

0.437

AC:

446944

AN:

1021836

Other (OTH)

AF:

0.422

AC:

24091

AN:

57060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

16495

32991

49486

65982

82477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13122

26244

39366

52488

65610

<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:

0.424

AC:

64454

AN:

152086

Hom.:

13962

Cov.:

AF XY:

0.426

AC XY:

31673

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.400

AC:

16595

AN:

41448

American (AMR)

AF:

0.409

AC:

6258

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.427

AC:

1482

AN:

3468

East Asian (EAS)

AF:

0.318

AC:

1644

AN:

5170

South Asian (SAS)

AF:

0.372

AC:

1789

AN:

4814

European-Finnish (FIN)

AF:

0.539

AC:

5701

AN:

10586

Middle Eastern (MID)

AF:

0.380

AC:

111

AN:

292

European-Non Finnish (NFE)

AF:

0.434

AC:

29531

AN:

67986

Other (OTH)

AF:

0.414

AC:

874

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1924

3848

5772

7696

9620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

616

1232

1848

2464

3080

<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:

0.435

Hom.:

2661

Bravo

AF:

0.416

Asia WGS

AF:

0.344

AC:

1198

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 23, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.0

(source)

DANN

Benign

0.74

PhyloP100

0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over