19-45529216-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000323060.4(OPA3):c.383A>T(p.His128Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: OPA3 ENST00000323060.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.543

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15652016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPA3	NM_001017989.3	c.383A>T	p.His128Leu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA3	ENST00000323060.4	c.383A>T	p.His128Leu	missense_variant	2/2	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000408 AC: 1 AN: 245124 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133576

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000908

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460152 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726478

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2021

The c.383A>T (p.H128L) alteration is located in exon 2 (coding exon 2) of the OPA3 gene. This alteration results from a A to T substitution at nucleotide position 383, causing the histidine (H) at amino acid position 128 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	5.6
Dann	Benign	0.85
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.17
Sift	Benign	0.068	T
Sift4G	Benign	0.26	T
Polyphen		0.15	B
Vest4		0.14
MutPred		0.45		Loss of MoRF binding (P = 0.1248);
MVP		0.64
MPC		0.96
ClinPred		0.20	T
GERP RS		2.5
gMVP		0.40

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs757040753; hg19: chr19-46032474;