dbSNP rs35801538: OPA1:p.Val140Val (chr3-193615742-G-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_130837.3(OPA1):c.420G>T(p.Val140Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00892 in 1,610,888 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0092 ( 88 hom. )

Consequence

OPA1
NM_130837.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.654

Publications

9 publications found

Variant links:

COSMIC-nc: COSV104418833

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: G2P, Labcorp Genetics (formerly Invitae)
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.063).

BP6

Variant 3-193615742-G-T is Benign according to our data. Variant chr3-193615742-G-T is described in ClinVar as Benign. ClinVar VariationId is 95725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.654 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00618 (941/152268) while in subpopulation SAS AF = 0.0104 (50/4816). AF 95% confidence interval is 0.00859. There are 7 homozygotes in GnomAd4. There are 451 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OPA1	NM_130837.3	MANE Select	c.420G>T	p.Val140Val	synonymous	Exon 3 of 31	NP_570850.2	O60313-10
OPA1	NM_130836.3		c.420G>T	p.Val140Val	synonymous	Exon 3 of 30	NP_570849.2	O60313-2
OPA1	NM_130835.3		c.420G>T	p.Val140Val	synonymous	Exon 3 of 30	NP_570848.1	E5KLJ9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OPA1	ENST00000361510.8	TSL:5 MANE Select	c.420G>T	p.Val140Val	synonymous	Exon 3 of 31	ENSP00000355324.2	O60313-10
OPA1	ENST00000361908.8	TSL:1	c.420G>T	p.Val140Val	synonymous	Exon 3 of 30	ENSP00000354681.3	O60313-2
OPA1	ENST00000968586.1		c.420G>T	p.Val140Val	synonymous	Exon 3 of 32	ENSP00000638645.1

Frequencies

GnomAD3 genomes

AF:

0.00618

AC:

940

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0102

Gnomad FIN

AF:

0.00623

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00919

Gnomad OTH

AF:

0.00862

GnomAD2 exomes

AF:

0.00836

AC:

2103

AN:

251424

AF XY:

0.00915

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.00411

Gnomad ASJ exome

AF:

0.0123

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00577

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.00921

AC:

13436

AN:

1458620

Hom.:

Cov.:

AF XY:

0.00948

AC XY:

6881

AN XY:

725850

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

33416

American (AMR)

AF:

0.00434

AC:

194

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

346

AN:

26102

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39598

South Asian (SAS)

AF:

0.0147

AC:

1269

AN:

86190

European-Finnish (FIN)

AF:

0.00597

AC:

319

AN:

53412

Middle Eastern (MID)

AF:

0.0169

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00957

AC:

10617

AN:

1109150

Other (OTH)

AF:

0.00896

AC:

540

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

635

1269

1904

2538

3173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

390

780

1170

1560

1950

<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:

0.00618

AC:

941

AN:

152268

Hom.:

Cov.:

AF XY:

0.00606

AC XY:

451

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41560

American (AMR)

AF:

0.00346

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0159

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.0104

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00623

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00919

AC:

625

AN:

68016

Other (OTH)

AF:

0.00853

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

106

158

211

264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00768

Hom.:

Bravo

AF:

0.00602

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0112

EpiControl

AF:

0.0104

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (4)

Autosomal dominant optic atrophy classic form (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

4.4

(source)

DANN

Benign

0.80

PhyloP100

-0.65

Mutation Taster

=99/1

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