2-63056092-C-T

Variant names:

• chr2-63056092-C-T
• rs1489653532
• NM_014562.4:c.841C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014562.4(OTX1):​c.841C>T​(p.His281Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OTX1 NM_014562.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27232945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTX1	NM_014562.4	c.841C>T	p.His281Tyr	missense_variant	Exon 5 of 5	ENST00000282549.7	NP_055377.1
OTX1	NM_001199770.2	c.841C>T	p.His281Tyr	missense_variant	Exon 5 of 5		NP_001186699.1
OTX1	NR_130153.2	n.1204C>T		non_coding_transcript_exon_variant	Exon 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTX1	ENST00000282549.7	c.841C>T	p.His281Tyr	missense_variant	Exon 5 of 5	1	NM_014562.4	ENSP00000282549.2
OTX1	ENST00000366671.7	c.841C>T	p.His281Tyr	missense_variant	Exon 5 of 5	3		ENSP00000355631.3
OTX1	ENST00000405984.8	n.*650C>T		non_coding_transcript_exon_variant	Exon 5 of 5	2		ENSP00000385782.4
OTX1	ENST00000405984.8	n.*650C>T		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000385782.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.841C>T (p.H281Y) alteration is located in exon 5 (coding exon 3) of the OTX1 gene. This alteration results from a C to T substitution at nucleotide position 841, causing the histidine (H) at amino acid position 281 to be replaced by a tyrosine (Y). 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	Benign	0.13
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.038
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	.;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.72	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.22	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.44	B;B
Vest4		0.36
MutPred		0.22		Gain of phosphorylation at H281 (P = 0.0254);Gain of phosphorylation at H281 (P = 0.0254);
MVP		0.83
ClinPred		0.44	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.085
gMVP		0.40

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: rs1489653532; hg19: chr2-63283227;