14-56801988-G-T

Variant names:

• chr14-56801988-G-T
• rs150982073
• NM_021728.4:c.641C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_021728.4(OTX2):​c.641C>A​(p.Thr214Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000381 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T214I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: OTX2 NM_021728.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 9.78
• Publications: 6 publications found

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]

OTX2 Gene-Disease associations (from GenCC):

• syndromic microphthalmia type 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Orphanet
• pituitary hormone deficiency, combined, 6

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• combined pituitary hormone deficiencies, genetic form

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated anophthalmia-microphthalmia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• patterned macular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• septooptic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.0457 (below the threshold of 3.09). Trascript score misZ: 1.6551 (below the threshold of 3.09). GenCC associations: The gene is linked to syndromic microphthalmia type 5, combined pituitary hormone deficiencies, genetic form, pituitary hormone deficiency, combined, 6, isolated anophthalmia-microphthalmia syndrome, septooptic dysplasia, patterned macular dystrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20600048).
• BP6: Variant 14-56801988-G-T is Benign according to our data. Variant chr14-56801988-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288894.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0004 (585/1461892) while in subpopulation NFE AF = 0.000495 (550/1112010). AF 95% confidence interval is 0.00046. There are 0 homozygotes in GnomAdExome4. There are 280 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 30 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021728.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTX2	NM_021728.4	MANE Select	c.641C>A	p.Thr214Asn	missense	Exon 5 of 5	NP_068374.1
	OTX2	NM_001270525.2		c.641C>A	p.Thr214Asn	missense	Exon 3 of 3	NP_001257454.1
	OTX2	NM_001270523.2		c.617C>A	p.Thr206Asn	missense	Exon 5 of 5	NP_001257452.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTX2	ENST00000672264.2	MANE Select	c.641C>A	p.Thr214Asn	missense	Exon 5 of 5	ENSP00000500115.1
	OTX2	ENST00000554845.2	TSL:1	c.641C>A	p.Thr214Asn	missense	Exon 3 of 3	ENSP00000451357.2
	OTX2	ENST00000339475.10	TSL:1	c.617C>A	p.Thr206Asn	missense	Exon 5 of 5	ENSP00000343819.5

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000255 AC: 64 AN: 251460 AF XY: 0.000235

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000400 AC: 585 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.000385 AC XY: 280 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000495 AC: 550 AN: 1112010

Other (OTH) AF: 0.000513 AC: 31 AN: 60396

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74330

African (AFR) AF: 0.000121 AC: 5 AN: 41428

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000358 Hom.: 0

Bravo AF: 0.000166

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000436

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Jul 07, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Anophthalmia-microphthalmia syndrome Uncertain:1

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 206 of the OTX2 protein (p.Thr206Asn). This variant is present in population databases (rs150982073, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with OTX2-related conditions. ClinVar contains an entry for this variant (Variation ID: 288894). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Syndromic microphthalmia type 5 Benign:1

May 28, 2019

Mendelics

Significance: Likely 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: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Inborn genetic diseases Benign:1

Jan 10, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	0.066
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.0	N
PhyloP100		9.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.21
Sift	Uncertain	0.015	D
Sift4G	Benign	0.12	T
Polyphen		0.083	B
Vest4		0.60
MVP		0.54
MPC		0.062
ClinPred		0.12	T
GERP RS		4.6
Varity_R		0.25
gMVP		0.61
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs150982073; hg19: chr14-57268706;