chr10-13100087-G-T

Position:

• chr10-13100087-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021980.4(OPTN):​c.-227G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 152,056 control chromosomes in the GnomAD database, including 2,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2550 hom., cov: 30)
  • Exomes 𝑓: 0.19 (9 hom.)
• Consequence: OPTN NM_021980.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.01

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 10-13100087-G-T is Benign according to our data. Variant chr10-13100087-G-T is described in ClinVar as [Benign]. Clinvar id is 299201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPTN	NM_001008211.1	c.-448G>T		5_prime_UTR_variant	1/16
OPTN	NM_001008213.1	c.-433G>T		5_prime_UTR_variant	1/16
OPTN	NM_021980.4	c.-227G>T		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPTN	ENST00000263036.9	c.-164+129G>T		intron_variant		2		P3
OPTN	ENST00000378764.6	c.-164+129G>T		intron_variant		5		A1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26431 AN: 151576 Hom.: 2553 Cov.: 30

Gnomad AFR AF: 0.0995

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.0888

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.192

GnomAD4 exome AF: 0.188 AC: 70 AN: 372 Hom.: 9 Cov.: 0 AF XY: 0.204 AC XY: 57 AN XY: 280

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.400

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.168

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.174 AC: 26424 AN: 151684 Hom.: 2550 Cov.: 30 AF XY: 0.170 AC XY: 12632 AN XY: 74138

Gnomad4 AFR AF: 0.0994

Gnomad4 AMR AF: 0.203

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.0891

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.221

Gnomad4 OTH AF: 0.190

Alfa AF: 0.0587 Hom.: 66

Bravo AF: 0.177

Asia WGS AF: 0.135 AC: 467 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Primary open angle glaucoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.21
DANN	Benign	0.76

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: rs3814657; hg19: chr10-13142087;