2-63054086-C-A

Variant names:

• chr2-63054086-C-A
• rs1272690593
• NM_014562.4:c.137C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014562.4(OTX1):​c.137C>A​(p.Thr46Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OTX1 NM_014562.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

Genes affected

OTX1 (HGNC:8521): (orthodenticle homeobox 1) This gene encodes a member of the bicoid sub-family of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and may play a role in brain and sensory organ development. A similar protein in mouse is required for proper brain and sensory organ development and can cause epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTX1	NM_014562.4	c.137C>A	p.Thr46Lys	missense_variant	Exon 4 of 5	ENST00000282549.7	NP_055377.1
OTX1	NM_001199770.2	c.137C>A	p.Thr46Lys	missense_variant	Exon 4 of 5		NP_001186699.1
OTX1	NR_130153.2	n.500C>A		non_coding_transcript_exon_variant	Exon 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTX1	ENST00000282549.7	c.137C>A	p.Thr46Lys	missense_variant	Exon 4 of 5	1	NM_014562.4	ENSP00000282549.2
OTX1	ENST00000366671.7	c.137C>A	p.Thr46Lys	missense_variant	Exon 4 of 5	3		ENSP00000355631.3
OTX1	ENST00000405984.8	n.252C>A		non_coding_transcript_exon_variant	Exon 4 of 5	2		ENSP00000385782.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459674 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.137C>A (p.T46K) alteration is located in exon 4 (coding exon 2) of the OTX1 gene. This alteration results from a C to A substitution at nucleotide position 137, causing the threonine (T) at amino acid position 46 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.70		Gain of methylation at T46 (P = 0.0101);Gain of methylation at T46 (P = 0.0101);
MVP		0.97
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.89
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs1272690593; hg19: chr2-63281221;