14-56801725-C-T

Variant names:

• chr14-56801725-C-T
• rs171978
• NM_021728.4:c.*10G>A

Variant summary

Our verdict is Benign. The variant received -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:7
• 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
OTX2	NM_021728.4	c.*10G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000672264.2	NP_068374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTX2	ENST00000672264.2	c.*10G>A		3_prime_UTR_variant	Exon 5 of 5		NM_021728.4	ENSP00000500115.1

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

GnomAD2 exomes AF: 0.0648 AC: 16225 AN: 250220 AF XY: 0.0663

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 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

African (AFR) AF: 0.0135 AC: 452 AN: 33460

American (AMR) AF: 0.0513 AC: 2295 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0698 AC: 1825 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0200 AC: 1728 AN: 86226

European-Finnish (FIN) AF: 0.0511 AC: 2726 AN: 53384

Middle Eastern (MID) AF: 0.0865 AC: 459 AN: 5306

European-Non Finnish (NFE) AF: 0.0993 AC: 110417 AN: 1111518

Other (OTH) AF: 0.0749 AC: 4516 AN: 60314

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

African (AFR) AF: 0.0161 AC: 671 AN: 41554

American (AMR) AF: 0.0696 AC: 1064 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 245 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5166

South Asian (SAS) AF: 0.0176 AC: 85 AN: 4830

European-Finnish (FIN) AF: 0.0532 AC: 564 AN: 10594

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0966 AC: 6573 AN: 68012

Other (OTH) AF: 0.0725 AC: 153 AN: 2110

Alfa AF: 0.0886 Hom.: 962

Bravo AF: 0.0639

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

OTX2-Related Syndromic Microphthalmia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Syndromic microphthalmia type 5 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 specified Benign:1

Jun 20, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pituitary hormone deficiency, combined, 6 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. -

Retinal dystrophy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.86
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Publications

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Other links and lift over

dbSNP: rs171978; hg19: chr14-57268443;