NM_021728.4:c.586G>A

Variant names:

• chr14-56802043-C-T
• rs397514463
• NM_021728.4:c.586G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PP2 PP3_Moderate BS2_Supporting

The NM_021728.4(OTX2):​c.586G>A​(p.Gly196Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G196V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: OTX2 NM_021728.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.12
• 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.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.848
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.586G>A	p.Gly196Arg	missense	Exon 5 of 5	NP_068374.1	F1T0D1
	OTX2	NM_001270525.2		c.586G>A	p.Gly196Arg	missense	Exon 3 of 3	NP_001257454.1	F1T0D1
	OTX2	NM_001270523.2		c.562G>A	p.Gly188Arg	missense	Exon 5 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.586G>A	p.Gly196Arg	missense	Exon 5 of 5	ENSP00000500115.1	P32243-2
	OTX2	ENST00000554845.2	TSL:1	c.586G>A	p.Gly196Arg	missense	Exon 3 of 3	ENSP00000451357.2	P32243-2
	OTX2	ENST00000339475.10	TSL:1	c.562G>A	p.Gly188Arg	missense	Exon 5 of 5	ENSP00000343819.5	P32243-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

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: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.046	D
Polyphen		0.96	D
Vest4		0.76
MutPred		0.64		Gain of catalytic residue at A190 (P = 0.0016)
MVP		0.94
MPC		0.29
ClinPred		0.95	D
GERP RS		6.1
Varity_R		0.28
gMVP		0.75
Mutation Taster		=49/51	disease causing

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: rs397514463; hg19: chr14-57268761;