14-56801725-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_021728.4(OTX2):c.*10G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0831 in 1,613,006 control chromosomes in the GnomAD database, including 6,404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (380 hom., cov: 32)
  • Exomes 𝑓: 0.085 (6024 hom.)
• Consequence: OTX2 NM_021728.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.02

Genes affected

OTX2 (HGNC:8522): (orthodenticle homeobox 2) This gene encodes a member of the bicoid subfamily of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and plays a role in brain, craniofacial, and sensory organ development. The encoded protein also influences the proliferation and differentiation of dopaminergic neuronal progenitor cells during mitosis. Mutations in this gene cause syndromic microphthalmia 5 (MCOPS5) and combined pituitary hormone deficiency 6 (CPHD6). This gene is also suspected of having an oncogenic role in medulloblastoma. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Pseudogenes of this gene are known to exist on chromosomes two and nine. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 14-56801725-C-T is Benign according to our data. Variant chr14-56801725-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 288866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTX2	NM_021728.4	c.*10G>A		3_prime_UTR_variant	5/5	ENST00000672264.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTX2	ENST00000672264.2	c.*10G>A		3_prime_UTR_variant	5/5		NM_021728.4	A1

Frequencies

GnomAD3 genomes AF: 0.0629 AC: 9564 AN: 152122 Hom.: 380 Cov.: 32

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.0698

Gnomad ASJ AF: 0.0706

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0532

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0966

Gnomad OTH AF: 0.0742

GnomAD3 exomes AF: 0.0648 AC: 16225 AN: 250220 Hom.: 692 AF XY: 0.0663 AC XY: 8998 AN XY: 135720

Gnomad AFR exome AF: 0.0128

Gnomad AMR exome AF: 0.0502

Gnomad ASJ exome AF: 0.0717

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0190

Gnomad FIN exome AF: 0.0515

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0785

GnomAD4 exome AF: 0.0852 AC: 124422 AN: 1460766 Hom.: 6024 Cov.: 31 AF XY: 0.0837 AC XY: 60801 AN XY: 726740

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.0513

Gnomad4 ASJ exome AF: 0.0698

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0200

Gnomad4 FIN exome AF: 0.0511

Gnomad4 NFE exome AF: 0.0993

Gnomad4 OTH exome AF: 0.0749

GnomAD4 genome AF: 0.0628 AC: 9557 AN: 152240 Hom.: 380 Cov.: 32 AF XY: 0.0607 AC XY: 4518 AN XY: 74420

Gnomad4 AFR AF: 0.0161

Gnomad4 AMR AF: 0.0696

Gnomad4 ASJ AF: 0.0706

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.0532

Gnomad4 NFE AF: 0.0966

Gnomad4 OTH AF: 0.0725

Alfa AF: 0.0913 Hom.: 801

Bravo AF: 0.0639

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

OTX2-Related Syndromic Microphthalmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Syndromic microphthalmia type 5 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 20, 2016

- -

Pituitary hormone deficiency, combined, 6 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Retinal dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	19
Dann	Benign	0.86

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs171978; hg19: chr14-57268443;