10-13124053-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001008212.2(OPTN):c.941A>T(p.Gln314Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,613,880 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

OPTN
NM_001008212.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: 7.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPTN	NM_001008212.2 link	c.941A>T	p.Gln314Leu	missense_variant	Exon 9 of 15	ENST00000378747.8	NP_001008213.1	Q96CV9-1
OPTN	NM_001008211.1 link	c.941A>T	p.Gln314Leu	missense_variant	Exon 10 of 16		NP_001008212.1	Q96CV9-1
OPTN	NM_001008213.1 link	c.941A>T	p.Gln314Leu	missense_variant	Exon 10 of 16		NP_001008214.1	Q96CV9-1
OPTN	NM_021980.4 link	c.941A>T	p.Gln314Leu	missense_variant	Exon 8 of 14		NP_068815.2	Q96CV9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPTN	ENST00000378747.8 link	c.941A>T	p.Gln314Leu	missense_variant	Exon 9 of 15	1	NM_001008212.2	ENSP00000368021.3		Q96CV9-1

Frequencies

GnomAD3 genomes

AF:

0.0000722

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000151

AC:

AN:

251158

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

158

AN:

1461610

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000119

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000219

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 09, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with amyotrophic lateral sclerosis. Computational tools predict that this variant is damaging. -

Motor neuron disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

case-control

Centre for Genomic and Experimental Medicine, University of Edinburgh

Aug 31, 2016

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2022

The p.Q314L variant (also known as c.941A>T), located in coding exon 7 of the OPTN gene, results from an A to T substitution at nucleotide position 941. The glutamine at codon 314 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant amyotrophic lateral sclerosis; however, its contribution to the development of autosomal recessive amyotrophic lateral sclerosis is uncertain. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2024

This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 314 of the OPTN protein (p.Gln314Leu). This variant is present in population databases (rs142812715, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of OPTN-related conditions (PMID: 21613650, 23138764, 25382069, 28089114, 31000212, 32028661, 33770234, 36133075, 36570531). ClinVar contains an entry for this variant (Variation ID: 266060). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OPTN 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

Uncertain

0.37

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.;D;.;D;D

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.84

.;.;.;T;.;T

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.86

D;D;D;D;D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.5

M;.;M;.;M;M

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-4.8

D;D;D;D;D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0050

D;D;D;D;D;D

Sift4G

Benign

0.15

T;T;T;T;T;T

Polyphen

1.0

D;D;D;D;D;D

Vest4

0.86

MVP

0.96

MPC

0.70

ClinPred

0.84

GERP RS

5.0

Varity_R

0.34

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over