chr10-13100251-G-A

Variant names:

• chr10-13100251-G-A
• rs11548142
• NM_001008212.2:c.-215G>A

Variant summary

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

The NM_001008212.2(OPTN):​c.-215G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,900 control chromosomes in the GnomAD database, including 3,544 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3521 hom., cov: 34)
  • Exomes 𝑓: 0.21 (23 hom.)
• Consequence: OPTN NM_001008212.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.169

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=-0.72).
• BP6: Variant 10-13100251-G-A is Benign according to our data. Variant chr10-13100251-G-A is described in ClinVar as [Benign]. Clinvar id is 299207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPTN	NM_001008212.2	c.-215G>A		5_prime_UTR_variant	Exon 1 of 15	ENST00000378747.8	NP_001008213.1
OPTN	NM_001008211.1	c.-284G>A		5_prime_UTR_variant	Exon 1 of 16		NP_001008212.1
OPTN	NM_001008213.1	c.-269G>A		5_prime_UTR_variant	Exon 1 of 16		NP_001008214.1
OPTN	NM_021980.4	c.-63G>A		5_prime_UTR_variant	Exon 1 of 14		NP_068815.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPTN	ENST00000378747	c.-215G>A		5_prime_UTR_variant	Exon 1 of 15	1	NM_001008212.2	ENSP00000368021.3

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29731 AN: 152076 Hom.: 3518 Cov.: 34

Gnomad AFR AF: 0.0523

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.224

GnomAD4 exome AF: 0.205 AC: 147 AN: 716 Hom.: 23 Cov.: 0 AF XY: 0.221 AC XY: 101 AN XY: 456

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.100

Gnomad4 SAS exome AF: 0.170

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.236

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.195 AC: 29729 AN: 152184 Hom.: 3521 Cov.: 34 AF XY: 0.195 AC XY: 14482 AN XY: 74398

Gnomad4 AFR AF: 0.0521

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.310

Gnomad4 EAS AF: 0.176

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.263

Gnomad4 OTH AF: 0.226

Alfa AF: 0.218 Hom.: 1229

Bravo AF: 0.194

Asia WGS AF: 0.191 AC: 660 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 12 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Primary open angle glaucoma Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.72
CADD	Benign	15
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs11548142; hg19: chr10-13142251;