chr2-63056287-C-A

Position:

• chr2-63056287-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014562.4(OTX1):​c.1036C>A​(p.Gln346Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTX1 NM_014562.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90

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]

OTX1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTX1	NM_014562.4	c.1036C>A	p.Gln346Lys	missense_variant	5/5	ENST00000282549.7	NP_055377.1
OTX1	NM_001199770.2	c.1036C>A	p.Gln346Lys	missense_variant	5/5		NP_001186699.1
OTX1	NR_130153.2	n.1399C>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTX1	ENST00000282549.7	c.1036C>A	p.Gln346Lys	missense_variant	5/5	1	NM_014562.4	ENSP00000282549.2
OTX1	ENST00000366671.7	c.1036C>A	p.Gln346Lys	missense_variant	5/5	3		ENSP00000355631.3
OTX1	ENST00000405984.8	n.*845C>A		non_coding_transcript_exon_variant	5/5	2		ENSP00000385782.4
OTX1	ENST00000405984.8	n.*845C>A		3_prime_UTR_variant	5/5	2		ENSP00000385782.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2024

The c.1036C>A (p.Q346K) alteration is located in exon 5 (coding exon 3) of the OTX1 gene. This alteration results from a C to A substitution at nucleotide position 1036, causing the glutamine (Q) at amino acid position 346 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	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.92	P;P
Vest4		0.77
MutPred		0.65		Loss of catalytic residue at Q346 (P = 0.0187);Loss of catalytic residue at Q346 (P = 0.0187);
MVP		0.92
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.67
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-63283422;