19-45553823-A-G

Variant names:

• chr19-45553823-A-G
• rs3826860
• NM_025136.4:c.231T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000263275.5(OPA3):​c.231T>C​(p.Ala77Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 1,612,564 control chromosomes in the GnomAD database, including 359,236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38366 hom., cov: 34)
  • Exomes 𝑓: 0.66 (320870 hom.)
• Consequence: OPA3 ENST00000263275.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.930
• Publications: 24 publications found

Genes affected

OPA3 (HGNC:8142): (outer mitochondrial membrane lipid metabolism regulator OPA3) The mouse ortholog of this protein co-purifies with the mitochondrial inner membrane. Mutations in this gene have been shown to result in 3-methylglutaconic aciduria type III and autosomal dominant optic atrophy and cataract. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

OPA3 Gene-Disease associations (from GenCC):

• optic atrophy 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• 3-methylglutaconic aciduria type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-45553823-A-G is Benign according to our data. Variant chr19-45553823-A-G is described in ClinVar as Benign. ClinVar VariationId is 21709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.93 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000263275.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA3	NM_025136.4	MANE Select	c.231T>C	p.Ala77Ala	synonymous	Exon 2 of 2	NP_079412.1
	OPA3	NM_001017989.3		c.143-24367T>C		intron	N/A	NP_001017989.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA3	ENST00000263275.5	TSL:1 MANE Select	c.231T>C	p.Ala77Ala	synonymous	Exon 2 of 2	ENSP00000263275.4
	OPA3	ENST00000323060.4	TSL:1	c.143-24367T>C		intron	N/A	ENSP00000319817.3
	OPA3	ENST00000544371.1	TSL:2	c.72T>C	p.Ala24Ala	synonymous	Exon 2 of 2	ENSP00000442839.1

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107273 AN: 152044 Hom.: 38312 Cov.: 34

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.761

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.869

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.761

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.642

Gnomad OTH AF: 0.687

GnomAD2 exomes AF: 0.710 AC: 174409 AN: 245770 AF XY: 0.701

Gnomad AFR exome AF: 0.775

Gnomad AMR exome AF: 0.830

Gnomad ASJ exome AF: 0.590

Gnomad EAS exome AF: 0.875

Gnomad FIN exome AF: 0.755

Gnomad NFE exome AF: 0.649

Gnomad OTH exome AF: 0.675

GnomAD4 exome AF: 0.660 AC: 963907 AN: 1460402 Hom.: 320870 Cov.: 67 AF XY: 0.659 AC XY: 478904 AN XY: 726440

African (AFR) AF: 0.770 AC: 25750 AN: 33462

American (AMR) AF: 0.821 AC: 36658 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 15421 AN: 26092

East Asian (EAS) AF: 0.840 AC: 33310 AN: 39676

South Asian (SAS) AF: 0.666 AC: 57446 AN: 86202

European-Finnish (FIN) AF: 0.753 AC: 39910 AN: 52970

Middle Eastern (MID) AF: 0.576 AC: 3325 AN: 5768

European-Non Finnish (NFE) AF: 0.641 AC: 712184 AN: 1111262

Other (OTH) AF: 0.661 AC: 39903 AN: 60344

GnomAD4 genome AF: 0.706 AC: 107386 AN: 152162 Hom.: 38366 Cov.: 34 AF XY: 0.713 AC XY: 53064 AN XY: 74390

African (AFR) AF: 0.769 AC: 31925 AN: 41520

American (AMR) AF: 0.761 AC: 11638 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 2076 AN: 3468

East Asian (EAS) AF: 0.869 AC: 4494 AN: 5172

South Asian (SAS) AF: 0.683 AC: 3299 AN: 4832

European-Finnish (FIN) AF: 0.761 AC: 8060 AN: 10596

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.642 AC: 43657 AN: 67968

Other (OTH) AF: 0.691 AC: 1460 AN: 2114

Alfa AF: 0.655 Hom.: 10742

Bravo AF: 0.713

Asia WGS AF: 0.823 AC: 2861 AN: 3478

EpiCase AF: 0.636

EpiControl AF: 0.640

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	3-Methylglutaconic aciduria type 3 (3)
-	-	3	not specified (3)
-	-	2	Optic atrophy 3 (2)
-	-	1	3-Methylglutaconic aciduria type 3;C1833809:Optic atrophy 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.82
DANN	Benign	0.66
PhyloP100		-0.93
Mutation Taster		=100/0	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: rs3826860; hg19: chr19-46057081; COSMIC: COSV54398768;