14-56801394-TG-T

Position:

• chr14-56801394-TG-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_021728.4(OTX2):​c.*340del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 370,246 control chromosomes in the GnomAD database, including 292 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (95 hom., cov: 32)
  • Exomes 𝑓: 0.030 (197 hom.)
• Consequence: OTX2 NM_021728.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.96

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 -16 ACMG points.

• BP6: Variant 14-56801394-TG-T is Benign according to our data. Variant chr14-56801394-TG-T is described in ClinVar as [Likely_benign]. Clinvar id is 313414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTX2	NM_021728.4	c.*340del		3_prime_UTR_variant	5/5	ENST00000672264.2	NP_068374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTX2	ENST00000672264.2	c.*340del		3_prime_UTR_variant	5/5		NM_021728.4	ENSP00000500115	A1

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4104 AN: 152164 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0360

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.0570

Gnomad FIN AF: 0.0397

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.0287

GnomAD4 exome AF: 0.0296 AC: 6458 AN: 217964 Hom.: 197 Cov.: 0 AF XY: 0.0316 AC XY: 3727 AN XY: 117798

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.0309

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.124

Gnomad4 SAS exome AF: 0.0473

Gnomad4 FIN exome AF: 0.0391

Gnomad4 NFE exome AF: 0.0178

Gnomad4 OTH exome AF: 0.0275

GnomAD4 genome AF: 0.0270 AC: 4114 AN: 152282 Hom.: 95 Cov.: 32 AF XY: 0.0295 AC XY: 2200 AN XY: 74452

Gnomad4 AFR AF: 0.0195

Gnomad4 AMR AF: 0.0358

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.0568

Gnomad4 FIN AF: 0.0397

Gnomad4 NFE AF: 0.0187

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0129 Hom.: 3

Bravo AF: 0.0260

Asia WGS AF: 0.101 AC: 349 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

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, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2021

See Variant Classification Assertion Criteria. -

Retinal dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Combined Pituitary Hormone Deficiency, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3215889; hg19: chr14-57268112;