rs7624750

Variant names:

• chr3-193617202-G-A
• rs7624750
• NM_130837.3:c.473G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_130837.3(OPA1):​c.473G>A​(p.Ser158Asn) variant causes a missense change. The variant allele was found at a frequency of 0.471 in 1,604,536 control chromosomes in the GnomAD database, including 180,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S158I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.50 (19086 hom., cov: 33)
  • Exomes 𝑓: 0.47 (161018 hom.)
• Consequence: OPA1 NM_130837.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.16
• Publications: 66 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=3.4299493E-4).
• BP6: Variant 3-193617202-G-A is Benign according to our data. Variant chr3-193617202-G-A is described in ClinVar as Benign. ClinVar VariationId is 95727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	NM_130837.3	MANE Select	c.473G>A	p.Ser158Asn	missense	Exon 4 of 31	NP_570850.2
	OPA1	NM_130836.3		c.473G>A	p.Ser158Asn	missense	Exon 4 of 30	NP_570849.2
	OPA1	NM_130834.3		c.473G>A	p.Ser158Asn	missense	Exon 4 of 30	NP_570847.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	ENST00000361510.8	TSL:5 MANE Select	c.473G>A	p.Ser158Asn	missense	Exon 4 of 31	ENSP00000355324.2
	OPA1	ENST00000361908.8	TSL:1	c.473G>A	p.Ser158Asn	missense	Exon 4 of 30	ENSP00000354681.3
	OPA1	ENST00000968586.1		c.473G>A	p.Ser158Asn	missense	Exon 4 of 32	ENSP00000638645.1

Frequencies

GnomAD3 genomes AF: 0.496 AC: 75338 AN: 151890 Hom.: 19057 Cov.: 33

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.472

GnomAD2 exomes AF: 0.467 AC: 117207 AN: 250714 AF XY: 0.464

Gnomad AFR exome AF: 0.569

Gnomad AMR exome AF: 0.420

Gnomad ASJ exome AF: 0.468

Gnomad EAS exome AF: 0.395

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.457

GnomAD4 exome AF: 0.468 AC: 680279 AN: 1452528 Hom.: 161018 Cov.: 31 AF XY: 0.467 AC XY: 337540 AN XY: 723230

African (AFR) AF: 0.577 AC: 19148 AN: 33206

American (AMR) AF: 0.422 AC: 18834 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 12360 AN: 26040

East Asian (EAS) AF: 0.357 AC: 14139 AN: 39558

South Asian (SAS) AF: 0.438 AC: 37668 AN: 85940

European-Finnish (FIN) AF: 0.572 AC: 30546 AN: 53378

Middle Eastern (MID) AF: 0.418 AC: 2401 AN: 5750

European-Non Finnish (NFE) AF: 0.468 AC: 517000 AN: 1103990

Other (OTH) AF: 0.469 AC: 28183 AN: 60042

GnomAD4 genome AF: 0.496 AC: 75418 AN: 152008 Hom.: 19086 Cov.: 33 AF XY: 0.496 AC XY: 36867 AN XY: 74290

African (AFR) AF: 0.566 AC: 23441 AN: 41442

American (AMR) AF: 0.443 AC: 6774 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1604 AN: 3472

East Asian (EAS) AF: 0.397 AC: 2057 AN: 5180

South Asian (SAS) AF: 0.426 AC: 2054 AN: 4822

European-Finnish (FIN) AF: 0.573 AC: 6042 AN: 10546

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.468 AC: 31808 AN: 67950

Other (OTH) AF: 0.473 AC: 1000 AN: 2114

Alfa AF: 0.472 Hom.: 58800

Bravo AF: 0.491

TwinsUK AF: 0.463 AC: 1717

ALSPAC AF: 0.469 AC: 1807

ESP6500AA AF: 0.562 AC: 2474

ESP6500EA AF: 0.464 AC: 3988

ExAC AF: 0.468 AC: 56814

Asia WGS AF: 0.426 AC: 1480 AN: 3478

EpiCase AF: 0.453

EpiControl AF: 0.450

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Autosomal dominant optic atrophy classic form (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.75
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.031
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.00034	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.2
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.21
Sift	Benign	0.64	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.089
ClinPred		0.015	T
GERP RS		3.6
Varity_R		0.031
gMVP		0.093
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7624750; hg19: chr3-193334991; COSMIC: COSV62479043; COSMIC: COSV62479043;