10-13109124-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001008212.2(OPTN):c.2T>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000547 in 1,461,778 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: OPTN NM_001008212.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.81

Genes affected

OPTN (HGNC:17142): (optineurin) This gene encodes the coiled-coil containing protein optineurin. Optineurin may play a role in normal-tension glaucoma and adult-onset primary open angle glaucoma. Optineurin interacts with adenovirus E3-14.7K protein and may utilize tumor necrosis factor-alpha or Fas-ligand pathways to mediate apoptosis, inflammation or vasoconstriction. Optineurin may also function in cellular morphogenesis and membrane trafficking, vesicle trafficking, and transcription activation through its interactions with the RAB8, huntingtin, and transcription factor IIIA proteins. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPTN	NM_001008212.2	c.2T>A	p.Met1?	start_lost	3/15	ENST00000378747.8
OPTN	NM_001008211.1	c.2T>A	p.Met1?	start_lost	4/16
OPTN	NM_001008213.1	c.2T>A	p.Met1?	start_lost	4/16
OPTN	NM_021980.4	c.2T>A	p.Met1?	start_lost	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPTN	ENST00000378747.8	c.2T>A	p.Met1?	start_lost	3/15	1	NM_001008212.2	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

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: 0.00000629

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary open angle glaucoma;C1842026:Glaucoma 1, open angle, E;C3150692:Amyotrophic lateral sclerosis type 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2023

This sequence change affects the initiator methionine of the OPTN mRNA. The next in-frame methionine is located at codon 44. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with OPTN-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Benign	0.12	T;.;T;.;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Benign	-1.8	N;N;N;N;N;N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.85
MutPred		0.42		Gain of ubiquitination at M1 (P = 0.0048);Gain of ubiquitination at M1 (P = 0.0048);Gain of ubiquitination at M1 (P = 0.0048);Gain of ubiquitination at M1 (P = 0.0048);Gain of ubiquitination at M1 (P = 0.0048);Gain of ubiquitination at M1 (P = 0.0048);
MVP		0.98
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs946553408; hg19: chr10-13151124;