chr3-193667177-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS1

The NM_130837.3(OPA1):c.2880A>G(p.Arg960Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,536,586 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R960R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

OPA1
NM_130837.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.393

Publications

4 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: 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:

ENSG00000306963 (HGNC:):

ENSG00000306963 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP6

Variant 3-193667177-A-G is Benign according to our data. Variant chr3-193667177-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00108 (165/152268) while in subpopulation AFR AF = 0.00241 (100/41556). AF 95% confidence interval is 0.00202. There are 0 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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	UniProt
OPA1	NM_130837.3	MANE Select	c.2880A>G	p.Arg960Arg	synonymous	Exon 29 of 31	NP_570850.2	O60313-10
OPA1	NM_130836.3		c.2826A>G	p.Arg942Arg	synonymous	Exon 28 of 30	NP_570849.2	O60313-2
OPA1	NM_130835.3		c.2772A>G	p.Arg924Arg	synonymous	Exon 28 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.2880A>G	p.Arg960Arg	synonymous	Exon 29 of 31	ENSP00000355324.2	O60313-10
OPA1	ENST00000361908.8	TSL:1	c.2826A>G	p.Arg942Arg	synonymous	Exon 28 of 30	ENSP00000354681.3	O60313-2
OPA1	ENST00000968586.1		c.2895A>G	p.Arg965Arg	synonymous	Exon 30 of 32	ENSP00000638645.1

Frequencies

GnomAD3 genomes

AF:

0.00108

AC:

165

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000625

AC:

157

AN:

251380

AF XY:

0.000501

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00486

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000329

AC:

456

AN:

1384318

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

208

AN XY:

693594

show subpopulations

African (AFR)

AF:

0.00203

AC:

AN:

31956

American (AMR)

AF:

0.00143

AC:

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.00585

AC:

150

AN:

25660

East Asian (EAS)

AF:

0.00

AC:

AN:

39310

South Asian (SAS)

AF:

0.00

AC:

AN:

84728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.000713

AC:

AN:

5612

European-Non Finnish (NFE)

AF:

0.000114

AC:

119

AN:

1041382

Other (OTH)

AF:

0.000936

AC:

AN:

57672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00108

AC:

165

AN:

152268

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00241

AC:

100

AN:

41556

American (AMR)

AF:

0.00183

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68010

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.00112

Hom.:

Bravo

AF:

0.00130

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Autosomal dominant optic atrophy classic form (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

0.39

PromoterAI

-0.012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.28

Position offset: -3

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