Variant rs786205611 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000378747.8(OPTN):c.918_922del(p.Thr307SerfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000657 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

OPTN
ENST00000378747.8 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.78

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-13124028-GTGACA-G is Pathogenic according to our data. Variant chr10-13124028-GTGACA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
OPTN	NM_001008212.2 linkuse as main transcript	c.918_922del	p.Thr307SerfsTer3	frameshift_variant	9/15	ENST00000378747.8	NP_001008213.1
OPTN	NM_001008211.1 linkuse as main transcript	c.918_922del	p.Thr307SerfsTer3	frameshift_variant	10/16		NP_001008212.1
OPTN	NM_001008213.1 linkuse as main transcript	c.918_922del	p.Thr307SerfsTer3	frameshift_variant	10/16		NP_001008214.1
OPTN	NM_021980.4 linkuse as main transcript	c.918_922del	p.Thr307SerfsTer3	frameshift_variant	8/14		NP_068815.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPTN	ENST00000378747.8 linkuse as main transcript	c.918_922del	p.Thr307SerfsTer3	frameshift_variant	9/15	1	NM_001008212.2	ENSP00000368021	P3	Q96CV9-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152200

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:

0.0000147

Gnomad OTH

AF:

0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 12

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 25, 2024

- -

not provided

Pathogenic:1

Likely pathogenic, flagged submission

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

This sequence change creates a premature translational stop signal (p.Thr307Serfs*3) in the OPTN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OPTN are known to be pathogenic (PMID: 20428114). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 35896380). ClinVar contains an entry for this variant (Variation ID: 191266). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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