14-56802340-G-C

Variant names:

• chr14-56802340-G-C
• rs104894464
• NM_021728.4:c.289C>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_021728.4(OTX2):​c.289C>G​(p.Arg97Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R97P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTX2 NM_021728.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.84
• Publications: 13 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_021728.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-56802339-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4083384.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 14-56802340-G-C is Pathogenic according to our data. Variant chr14-56802340-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 9516.Status of the report is no_assertion_criteria_provided, 0 stars.

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.289C>G	p.Arg97Gly	missense	Exon 5 of 5	NP_068374.1
	OTX2	NM_001270525.2		c.289C>G	p.Arg97Gly	missense	Exon 3 of 3	NP_001257454.1
	OTX2	NM_001270523.2		c.265C>G	p.Arg89Gly	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.289C>G	p.Arg97Gly	missense	Exon 5 of 5	ENSP00000500115.1
	OTX2	ENST00000554845.2	TSL:1	c.289C>G	p.Arg97Gly	missense	Exon 3 of 3	ENSP00000451357.2
	OTX2	ENST00000339475.10	TSL:1	c.265C>G	p.Arg89Gly	missense	Exon 5 of 5	ENSP00000343819.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Syndromic microphthalmia type 5 Pathogenic:1

Oct 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		4.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.015	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.83		Gain of catalytic residue at F86 (P = 0.0092)
MVP		1.0
MPC		2.4
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.87
gMVP		0.95
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs104894464; hg19: chr14-57269058;