3-193615016-T-G

Variant names:

• chr3-193615016-T-G
• rs77173739
• NM_130837.3:c.326T>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP3 BP4_Strong

The NM_130837.3(OPA1):​c.326T>G​(p.Val109Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OPA1 NM_130837.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.07

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0130337775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA1	NM_130837.3	c.326T>G	p.Val109Gly	missense_variant	Exon 2 of 31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.326T>G	p.Val109Gly	missense_variant	Exon 2 of 31	5	NM_130837.3	ENSP00000355324.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.000883 AC: 219 AN: 247902 Hom.: 0 AF XY: 0.000573 AC XY: 77 AN XY: 134486

Gnomad AFR exome AF: 0.00259

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00177

Gnomad NFE exome AF: 0.000974

Gnomad OTH exome AF: 0.00198

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000150 AC: 219 AN: 1461590 Hom.: 0 Cov.: 33 AF XY: 0.000177 AC XY: 129 AN XY: 727120

Gnomad4 AFR exome AF: 0.0000299

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: 0.00361

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000160 Hom.: 0

ExAC AF: 0.0111 AC: 1345

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;.;D;D;.;T;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;T;D;.;D;D;D;T;D
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;M;M;M;M;M;.;M;M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D;D;.;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;.;D;.
Polyphen		0.61	P;.;.;D;D;.;.;.;.;.
Vest4		0.53
MPC		0.15
ClinPred		0.050	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs77173739; hg19: chr3-193332805;