10-13100153-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021980.4(OPTN):c.-161T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 153,162 control chromosomes in the GnomAD database, including 10,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10237 hom., cov: 33)
  • Exomes 𝑓: 0.30 (64 hom.)
• Consequence: OPTN NM_021980.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -2.49

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-13100153-T-C is Benign according to our data. Variant chr10-13100153-T-C is described in ClinVar as [Benign]. Clinvar id is 299202.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPTN	NM_001008211.1	c.-382T>C		5_prime_UTR_variant	1/16
OPTN	NM_001008213.1	c.-367T>C		5_prime_UTR_variant	1/16
OPTN	NM_021980.4	c.-161T>C		5_prime_UTR_variant	1/14
OPTN	NM_001008212.2			upstream_gene_variant		ENST00000378747.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPTN	ENST00000378747.8			upstream_gene_variant		1	NM_001008212.2	P3

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55575 AN: 151918 Hom.: 10229 Cov.: 33

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.372

GnomAD4 exome AF: 0.302 AC: 343 AN: 1134 Hom.: 64 Cov.: 0 AF XY: 0.308 AC XY: 208 AN XY: 676

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.333

Gnomad4 EAS exome AF: 0.333

Gnomad4 SAS exome AF: 0.292

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.317

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.366 AC: 55615 AN: 152028 Hom.: 10237 Cov.: 33 AF XY: 0.363 AC XY: 26984 AN XY: 74316

Gnomad4 AFR AF: 0.399

Gnomad4 AMR AF: 0.400

Gnomad4 ASJ AF: 0.346

Gnomad4 EAS AF: 0.310

Gnomad4 SAS AF: 0.291

Gnomad4 FIN AF: 0.361

Gnomad4 NFE AF: 0.350

Gnomad4 OTH AF: 0.371

Alfa AF: 0.362 Hom.: 2637

Bravo AF: 0.375

Asia WGS AF: 0.287 AC: 988 AN: 3454

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Primary open angle glaucoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.88
Cadd	Benign	0.80
Dann	Benign	0.26

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: rs71492279; hg19: chr10-13142153;