2-63056069-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014562.4(OTX1):​c.818C>G​(p.Ala273Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000197 in 152,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: OTX1 NM_014562.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14628974).

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>G	p.Ala273Gly	missense	Exon 5 of 5	NP_055377.1	P32242
	OTX1	NM_001199770.2		c.818C>G	p.Ala273Gly	missense	Exon 5 of 5	NP_001186699.1	P32242
	OTX1	NR_130153.2		n.1181C>G		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>G	p.Ala273Gly	missense	Exon 5 of 5	ENSP00000282549.2	P32242
	OTX1	ENST00000366671.7	TSL:3	c.818C>G	p.Ala273Gly	missense	Exon 5 of 5	ENSP00000355631.3	P32242
	OTX1	ENST00000946233.1		c.818C>G	p.Ala273Gly	missense	Exon 5 of 5	ENSP00000616292.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74264

African (AFR) AF: 0.0000724 AC: 3 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.0	N
PhyloP100		6.0
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	0.78	T
Polyphen		0.089	B
Vest4		0.12
MutPred		0.54		Loss of stability (P = 0.0469)
MVP		0.80
ClinPred		0.43	T
GERP RS		3.6
Varity_R		0.099
gMVP		0.28
Mutation Taster		=75/25	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;