19-45528866-T-C

Variant names:

• chr19-45528866-T-C
• rs73568948
• ENST00000323060.4:c.*190A>G

Variant summary

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

The NM_001017989.3(OPA3):​c.*190A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0928 in 614,348 control chromosomes in the GnomAD database, including 2,921 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (598 hom., cov: 31)
  • Exomes 𝑓: 0.096 (2323 hom.)
• Consequence: OPA3 NM_001017989.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.95
• Publications: 5 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, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 19-45528866-T-C is Benign according to our data. Variant chr19-45528866-T-C is described in ClinVar as Benign. ClinVar VariationId is 1263205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017989.3. 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
	OPA3	NM_001017989.3		c.*190A>G		3_prime_UTR	Exon 2 of 2	NP_001017989.2	Q9H6K4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA3	ENST00000323060.4	TSL:1	c.*190A>G		3_prime_UTR	Exon 2 of 2	ENSP00000319817.3	Q9H6K4-2

Frequencies

GnomAD3 genomes AF: 0.0832 AC: 12589 AN: 151380 Hom.: 596 Cov.: 31

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0584

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0928

Gnomad OTH AF: 0.0793

GnomAD4 exome AF: 0.0959 AC: 44407 AN: 462850 Hom.: 2323 Cov.: 6 AF XY: 0.0978 AC XY: 23644 AN XY: 241712

African (AFR) AF: 0.0524 AC: 615 AN: 11740

American (AMR) AF: 0.0535 AC: 852 AN: 15922

Ashkenazi Jewish (ASJ) AF: 0.0972 AC: 1264 AN: 13010

East Asian (EAS) AF: 0.0874 AC: 2545 AN: 29112

South Asian (SAS) AF: 0.135 AC: 5306 AN: 39186

European-Finnish (FIN) AF: 0.114 AC: 3441 AN: 30144

Middle Eastern (MID) AF: 0.0603 AC: 117 AN: 1940

European-Non Finnish (NFE) AF: 0.0940 AC: 27768 AN: 295542

Other (OTH) AF: 0.0952 AC: 2499 AN: 26254

GnomAD4 genome AF: 0.0831 AC: 12592 AN: 151498 Hom.: 598 Cov.: 31 AF XY: 0.0857 AC XY: 6343 AN XY: 74012

African (AFR) AF: 0.0531 AC: 2191 AN: 41266

American (AMR) AF: 0.0584 AC: 888 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 368 AN: 3468

East Asian (EAS) AF: 0.135 AC: 694 AN: 5144

South Asian (SAS) AF: 0.143 AC: 685 AN: 4782

European-Finnish (FIN) AF: 0.113 AC: 1188 AN: 10494

Middle Eastern (MID) AF: 0.0411 AC: 12 AN: 292

European-Non Finnish (NFE) AF: 0.0928 AC: 6295 AN: 67834

Other (OTH) AF: 0.0852 AC: 179 AN: 2102

Alfa AF: 0.0631 Hom.: 87

Bravo AF: 0.0779

Asia WGS AF: 0.171 AC: 595 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.6
DANN	Benign	0.80
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs73568948; hg19: chr19-46032124; COSMIC: COSV55606478; COSMIC: COSV55606478;