rs780333963

Positions:

• chr3-193637279-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_130837.3(OPA1):​c.1033C>T​(p.Arg345Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R345Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: OPA1 NM_130837.3 missense, splice_region
• Scores: Splicing: ADA: 0.04713
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.76

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.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_130837.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-193637280-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 3-193637279-C-T is Pathogenic according to our data. Variant chr3-193637279-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402217.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-193637279-C-T is described in Lovd as [Pathogenic]. Variant chr3-193637279-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPA1	NM_130837.3	c.1033C>T	p.Arg345Trp	missense_variant, splice_region_variant	10/31	ENST00000361510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA1	ENST00000361510.8	c.1033C>T	p.Arg345Trp	missense_variant, splice_region_variant	10/31	5	NM_130837.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250406 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135304

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1448260 Hom.: 0 Cov.: 25 AF XY: 0.00000555 AC XY: 4 AN XY: 721230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;.;D;D;.;.;.;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.5	D;D;D;.;D;D;.;.;.;.;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;.;D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;D;D;.;.;.;.;.
Polyphen		1.0	D;.;.;D;D;.;.;.;.;.;.
Vest4		0.92
MutPred		0.81		.;.;Gain of catalytic residue at L343 (P = 0.0159);.;.;.;.;.;.;.;.;
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.88
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.047
dbscSNV1_RF	Benign	0.35
SpliceAI score (max)		0.010		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: rs780333963; hg19: chr3-193355068; COSMIC: COSV100655292; COSMIC: COSV100655292;