2-63056069-C-T

Variant names:

• chr2-63056069-C-T
• rs1003224172
• NM_014562.4:c.818C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014562.4(OTX1):​c.818C>T​(p.Ala273Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. A273G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTX1 NM_014562.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.97
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.266186).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014562.4. 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
	OTX1	NM_014562.4	MANE Select	c.818C>T	p.Ala273Val	missense	Exon 5 of 5	NP_055377.1	P32242
	OTX1	NM_001199770.2		c.818C>T	p.Ala273Val	missense	Exon 5 of 5	NP_001186699.1	P32242
	OTX1	NR_130153.2		n.1181C>T		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTX1	ENST00000282549.7	TSL:1 MANE Select	c.818C>T	p.Ala273Val	missense	Exon 5 of 5	ENSP00000282549.2	P32242
	OTX1	ENST00000366671.7	TSL:3	c.818C>T	p.Ala273Val	missense	Exon 5 of 5	ENSP00000355631.3	P32242
	OTX1	ENST00000946233.1		c.818C>T	p.Ala273Val	missense	Exon 5 of 5	ENSP00000616292.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.024
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.0	N
PhyloP100		6.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.27
Sift	Benign	0.040	D
Sift4G	Benign	0.062	T
Polyphen		0.34	B
Vest4		0.15
MutPred		0.57		Loss of glycosylation at P269 (P = 0.1286)
MVP		0.86
ClinPred		0.64	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.40
Mutation Taster		=79/21	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: rs1003224172; hg19: chr2-63283204;