rs267606929

chr10-13132098-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_001008212.2(OPTN):c.1433A>G(p.Glu478Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,118 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OPTN NM_001008212.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.33

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a helix (size 50) in uniprot entity OPTN_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001008212.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 10-13132098-A-G is Pathogenic according to our data. Variant chr10-13132098-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 7102.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-13132098-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPTN	NM_001008212.2	c.1433A>G	p.Glu478Gly	missense_variant	13/15	ENST00000378747.8
OPTN	NM_001008211.1	c.1433A>G	p.Glu478Gly	missense_variant	14/16
OPTN	NM_001008213.1	c.1433A>G	p.Glu478Gly	missense_variant	14/16
OPTN	NM_021980.4	c.1433A>G	p.Glu478Gly	missense_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPTN	ENST00000378747.8	c.1433A>G	p.Glu478Gly	missense_variant	13/15	1	NM_001008212.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461118 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726876

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

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: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 12 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 28, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 13, 2010	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.;D;.;D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.5	D;D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.94
MutPred		0.33		Gain of catalytic residue at A477 (P = 0.0315);.;Gain of catalytic residue at A477 (P = 0.0315);.;Gain of catalytic residue at A477 (P = 0.0315);Gain of catalytic residue at A477 (P = 0.0315);
MVP		1.0
MPC		0.54
ClinPred		1.0	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.67

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: rs267606929; hg19: chr10-13174098;