rs747481280

Variant names:

• chr10-13132068-T-G
• rs747481280
• NM_001008212.2:c.1403T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PP5

The NM_001008212.2(OPTN):​c.1403T>G​(p.Met468Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000616 in 1,459,930 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M468V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: OPTN NM_001008212.2 missense, splice_region
• Scores: Splicing: ADA: 0.5109
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.34
• Publications: 3 publications found

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]

OPTN Gene-Disease associations (from GenCC):

• glaucoma, normal tension, susceptibility to

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• amyotrophic lateral sclerosis type 12

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• glaucoma 1, open angle, E

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8
• PP5: Variant 10-13132068-T-G is Pathogenic according to our data. Variant chr10-13132068-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 266062.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPTN	NM_001008212.2	c.1403T>G	p.Met468Arg	missense_variant, splice_region_variant	Exon 13 of 15	ENST00000378747.8	NP_001008213.1
OPTN	NM_001008211.1	c.1403T>G	p.Met468Arg	missense_variant, splice_region_variant	Exon 14 of 16		NP_001008212.1
OPTN	NM_001008213.1	c.1403T>G	p.Met468Arg	missense_variant, splice_region_variant	Exon 14 of 16		NP_001008214.1
OPTN	NM_021980.4	c.1403T>G	p.Met468Arg	missense_variant, splice_region_variant	Exon 12 of 14		NP_068815.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPTN	ENST00000378747.8	c.1403T>G	p.Met468Arg	missense_variant, splice_region_variant	Exon 13 of 15	1	NM_001008212.2	ENSP00000368021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251436 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1459930 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726300

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1110656

Other (OTH) AF: 0.00 AC: 0 AN: 60272

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Motor neuron disease Pathogenic:1

Aug 31, 2016

Centre for Genomic and Experimental Medicine, University of Edinburgh

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

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

Oct 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 468 of the OPTN protein (p.Met468Arg). This variant is present in population databases (rs747481280, gnomAD 0.002%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 28089114, 29080331). ClinVar contains an entry for this variant (Variation ID: 266062). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.;D;.;D;D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	.;.;.;T;.;T
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.5	M;.;M;.;M;M
PhyloP100		5.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.013	D;D;D;D;D;D
Sift4G	Benign	0.12	T;T;T;T;T;T
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.90
MutPred		0.14		Gain of disorder (P = 0.0851);.;Gain of disorder (P = 0.0851);.;Gain of disorder (P = 0.0851);Gain of disorder (P = 0.0851);
MVP		0.99
MPC		0.72
ClinPred		0.88	D
GERP RS		6.2
Varity_R		0.93
gMVP		0.80
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.51
dbscSNV1_RF	Benign	0.64
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

Other links and lift over

dbSNP: rs747481280; hg19: chr10-13174068;