chr3-193593378-A-T

Position:

• chr3-193593378-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001354663.2(OPA1):​c.-430A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: OPA1 NM_001354663.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 3-193593378-A-T is Pathogenic according to our data. Variant chr3-193593378-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2504752.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-193593378-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPA1	NM_130837.3	c.1A>T	p.Met1?	initiator_codon_variant	1/31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.1A>T	p.Met1?	initiator_codon_variant	1/31	5	NM_130837.3	ENSP00000355324.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394704 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 687718

Gnomad4 AFR exome AF: 0.0000319

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2022

Identified in a patient with optic atrophy in published literature (Yu-Wai-Man et al., 2011); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21036400) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.0031	T;.;.;T;T;.;T;.;.;.
Eigen	Benign	0.069
Eigen_PC	Benign	0.17
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	0.41	D
PROVEAN	Benign	-0.63	N;N;N;N;N;N;N;.;N;.
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;.
Sift4G	Benign	0.42	T;T;T;T;T;T;D;.;T;.
Polyphen		0.17	B;.;.;B;B;.;.;.;.;.
Vest4		0.88
MutPred		0.99		Loss of catalytic residue at M1 (P = 0.1006);Loss of catalytic residue at M1 (P = 0.1006);Loss of catalytic residue at M1 (P = 0.1006);Loss of catalytic residue at M1 (P = 0.1006);Loss of catalytic residue at M1 (P = 0.1006);Loss of catalytic residue at M1 (P = 0.1006);Loss of catalytic residue at M1 (P = 0.1006);Loss of catalytic residue at M1 (P = 0.1006);Loss of catalytic residue at M1 (P = 0.1006);Loss of catalytic residue at M1 (P = 0.1006);
MVP		0.98
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.97
gMVP		0.35

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;