19-45529183-T-A

Variant names:

• chr19-45529183-T-A
• rs201888844
• ENST00000323060.4:c.416A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4_Strong BP6_Moderate

The NM_001017989.3(OPA3):​c.416A>T​(p.Gln139Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,610,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: OPA3 NM_001017989.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.58

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM1: In a chain Optic atrophy 3 protein (size 177) in uniprot entity OPA3_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_001017989.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.04952064).
• BP6: Variant 19-45529183-T-A is Benign according to our data. Variant chr19-45529183-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 790939.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA3	NM_001017989.3	c.416A>T	p.Gln139Leu	missense_variant	Exon 2 of 2		NP_001017989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA3	ENST00000323060.4	c.416A>T	p.Gln139Leu	missense_variant	Exon 2 of 2	1		ENSP00000319817.3

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152140 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000242 AC: 58 AN: 240124 AF XY: 0.000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00345

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000104

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000503

GnomAD4 exome AF: 0.000141 AC: 205 AN: 1458252 Hom.: 0 Cov.: 31 AF XY: 0.000153 AC XY: 111 AN XY: 725646

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33472

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44662

Gnomad4 ASJ exome AF: 0.00387 AC: 101 AN: 26086

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39692

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86224

Gnomad4 FIN exome AF: 0.0000793 AC: 4 AN: 50420

Gnomad4 NFE exome AF: 0.0000747 AC: 83 AN: 1111624

Gnomad4 Remaining exome AF: 0.000282 AC: 17 AN: 60320

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152140 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74326

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00432 AC: 0.00432277 AN: 0.00432277

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000132 AC: 0.000132306 AN: 0.000132306

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000451 Hom.: 0

Bravo AF: 0.000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000190 AC: 23

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-Methylglutaconic aciduria type 3;C1833809:Optic atrophy 3 Benign:1

Nov 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.043
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.46	T
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.76	P
Vest4		0.35
MVP		0.76
MPC		1.3
ClinPred		0.26	T
GERP RS		3.7
gMVP		0.50
Mutation Taster		=71/29	polymorphism

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs201888844; hg19: chr19-46032441;