rs77160003

Variant names:

• chr3-193593378-A-G
• rs77160003
• NM_130837.3:c.1A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-193593378-A-G
• chr3-193593378-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_130837.3(OPA1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OPA1 NM_130837.3 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.58

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 34 pathogenic variants. Next in-frame start position is after 125 codons. Genomic position: 193615695. Lost 0.122 part of the original CDS.
• PS1: Another start lost variant in NM_130837.3 (OPA1) was described as [Likely_pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA1	NM_130837.3	c.1A>G	p.Met1?	start_lost	Exon 1 of 31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.1A>G	p.Met1?	start_lost	Exon 1 of 31	5	NM_130837.3	ENSP00000355324.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0052	T;.;.;T;T;.;T;.;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.51	D
PROVEAN	Benign	-0.68	N;N;N;N;N;N;N;.;N;.
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;.
Sift4G	Uncertain	0.044	D;T;T;D;D;D;D;.;D;.
Polyphen		0.32	B;.;.;B;B;.;.;.;.;.
Vest4		0.87
MutPred		0.99		Loss of catalytic residue at M1 (P = 0.0629);Loss of catalytic residue at M1 (P = 0.0629);Loss of catalytic residue at M1 (P = 0.0629);Loss of catalytic residue at M1 (P = 0.0629);Loss of catalytic residue at M1 (P = 0.0629);Loss of catalytic residue at M1 (P = 0.0629);Loss of catalytic residue at M1 (P = 0.0629);Loss of catalytic residue at M1 (P = 0.0629);Loss of catalytic residue at M1 (P = 0.0629);Loss of catalytic residue at M1 (P = 0.0629);
MVP		0.98
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.96
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs77160003; hg19: chr3-193311167;