14-56804268-ACA-CC

Variant names:

• chr14-56804267-AAC-ACC
• NM_021728.4:c.193T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP3

The NM_021728.4(OTX2):​c.193T>G​(p.Phe65Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTX2 NM_021728.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.31
• Publications: 0 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: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• pituitary hormone deficiency, combined, 6

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_021728.4
• 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 pituitary hormone deficiency, combined, 6, syndromic microphthalmia type 5, septooptic dysplasia, combined pituitary hormone deficiencies, genetic form, patterned macular dystrophy, isolated anophthalmia-microphthalmia syndrome.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTX2	NM_021728.4	MANE Select	c.193T>G	p.Phe65Val	missense	Exon 4 of 5	NP_068374.1	F1T0D1
	OTX2	NM_001270525.2		c.193T>G	p.Phe65Val	missense	Exon 2 of 3	NP_001257454.1	F1T0D1
	OTX2	NM_001270523.2		c.169T>G	p.Phe57Val	missense	Exon 4 of 5	NP_001257452.1	P32243-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTX2	ENST00000672264.2	MANE Select	c.193T>G	p.Phe65Val	missense	Exon 4 of 5	ENSP00000500115.1	P32243-2
	OTX2	ENST00000554845.2	TSL:1	c.193T>G	p.Phe65Val	missense	Exon 2 of 3	ENSP00000451357.2	P32243-2
	OTX2	ENST00000339475.10	TSL:1	c.169T>G	p.Phe57Val	missense	Exon 4 of 5	ENSP00000343819.5	P32243-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr14-57270985;