10-13109129-C-T

Position:

• chr10-13109129-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001008212.2(OPTN):​c.7C>T​(p.His3Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: OPTN NM_001008212.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12572473).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPTN	NM_001008212.2	c.7C>T	p.His3Tyr	missense_variant	3/15	ENST00000378747.8
OPTN	NM_001008211.1	c.7C>T	p.His3Tyr	missense_variant	4/16
OPTN	NM_001008213.1	c.7C>T	p.His3Tyr	missense_variant	4/16
OPTN	NM_021980.4	c.7C>T	p.His3Tyr	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPTN	ENST00000378747.8	c.7C>T	p.His3Tyr	missense_variant	3/15	1	NM_001008212.2	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Dec 11, 2023

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 3 of the OPTN protein (p.His3Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of OPTN-related conditions (PMID: 22722621). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The tyrosine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	Benign	0.078
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.;T;.;T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.3	L;L;L;L;L;L
MutationTaster	Benign	0.96	N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Uncertain	0.50
Sift	Uncertain	0.0080	D;D;D;D;D;D
Sift4G	Benign	0.14	T;T;T;T;T;T
Polyphen		0.0030	B;B;B;B;B;B
Vest4		0.25
MutPred		0.29		Gain of phosphorylation at H3 (P = 0.0405);Gain of phosphorylation at H3 (P = 0.0405);Gain of phosphorylation at H3 (P = 0.0405);Gain of phosphorylation at H3 (P = 0.0405);Gain of phosphorylation at H3 (P = 0.0405);Gain of phosphorylation at H3 (P = 0.0405);
MVP		0.92
MPC		0.21
ClinPred		0.19	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1554768243; hg19: chr10-13151129;