dbSNP rs794726939: OPA1:p.Ala8Ser (chr3-193593399-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_130837.3(OPA1):c.22G>T(p.Ala8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

OPA1
NM_130837.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.663

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.22G>T	p.Ala8Ser	missense	Exon 1 of 31	NP_570850.2	O60313-10
OPA1	NM_130836.3		c.22G>T	p.Ala8Ser	missense	Exon 1 of 30	NP_570849.2	O60313-2
OPA1	NM_130835.3		c.22G>T	p.Ala8Ser	missense	Exon 1 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.22G>T	p.Ala8Ser	missense	Exon 1 of 31	ENSP00000355324.2	O60313-10
OPA1	ENST00000361908.8	TSL:1	c.22G>T	p.Ala8Ser	missense	Exon 1 of 30	ENSP00000354681.3	O60313-2
OPA1	ENST00000968586.1		c.22G>T	p.Ala8Ser	missense	Exon 1 of 32	ENSP00000638645.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1395034

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687894

African (AFR)

AF:

0.00

AC:

AN:

31362

American (AMR)

AF:

0.00

AC:

AN:

35464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25094

East Asian (EAS)

AF:

0.00

AC:

AN:

35476

South Asian (SAS)

AF:

0.00

AC:

AN:

78760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5008

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1076876

Other (OTH)

AF:

0.00

AC:

AN:

57710

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal dominant optic atrophy classic form (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

Eigen

Benign

-0.041

Eigen_PC

Benign

0.040

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.52

M_CAP

Benign

0.052

MetaRNN

Uncertain

0.49

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.81

PhyloP100

0.66

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.13

REVEL

Uncertain

0.62

Sift

Uncertain

0.019

Sift4G

Benign

0.59

Polyphen

0.0010

Vest4

0.41

MutPred

0.60

Gain of disorder (P = 0.0429)

MVP

0.96

MPC

0.088

ClinPred

0.64

GERP RS

3.8

PromoterAI

-0.012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.091

gMVP

0.49

Mutation Taster

=0/100

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over