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rs28757218

chr14-56805348-G-Achr14-56805348-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021728.4(OTX2):c.97+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,583,370 control chromosomes in the GnomAD database, including 171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 11 hom., cov: 32)
Exomes 𝑓: 0.014 ( 160 hom. )

Consequence

OTX2
NM_021728.4 intron

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.325
Variant links:
Genes affected
OTX2 (HGNC:8522): (orthodenticle homeobox 2) This gene encodes a member of the bicoid subfamily of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and plays a role in brain, craniofacial, and sensory organ development. The encoded protein also influences the proliferation and differentiation of dopaminergic neuronal progenitor cells during mitosis. Mutations in this gene cause syndromic microphthalmia 5 (MCOPS5) and combined pituitary hormone deficiency 6 (CPHD6). This gene is also suspected of having an oncogenic role in medulloblastoma. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Pseudogenes of this gene are known to exist on chromosomes two and nine. [provided by RefSeq, Jul 2012]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 14-56805348-G-A is Benign according to our data. Variant chr14-56805348-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 313422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-56805348-G-A is described in Lovd as [Benign].
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0103 (1564/152242) while in subpopulation AMR AF= 0.0176 (270/15298). AF 95% confidence interval is 0.0159. There are 11 homozygotes in gnomad4. There are 776 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 1565 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
OTX2NM_021728.4 linkuse as main transcriptc.97+12C>T intron_variant ENST00000672264.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
OTX2ENST00000672264.2 linkuse as main transcriptc.97+12C>T intron_variant NM_021728.4 A1P32243-2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0103
AC:
1565
AN:
152124
Hom.:
11
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00311
Gnomad AMI
AF:
0.00220
Gnomad AMR
AF:
0.0177
Gnomad ASJ
AF:
0.0181
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00186
Gnomad FIN
AF:
0.0123
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.0136
Gnomad OTH
AF:
0.0144
GnomAD3 exomes
AF:
0.0102
AC:
2554
AN:
250260
Hom.:
17
AF XY:
0.0101
AC XY:
1363
AN XY:
135428
show subpopulations
Gnomad AFR exome
AF:
0.00334
Gnomad AMR exome
AF:
0.00774
Gnomad ASJ exome
AF:
0.0185
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00272
Gnomad FIN exome
AF:
0.0114
Gnomad NFE exome
AF:
0.0145
Gnomad OTH exome
AF:
0.0134
GnomAD4 exome
AF:
0.0135
AC:
19359
AN:
1431128
Hom.:
160
Cov.:
27
AF XY:
0.0132
AC XY:
9394
AN XY:
713828
show subpopulations
Gnomad4 AFR exome
AF:
0.00243
Gnomad4 AMR exome
AF:
0.00788
Gnomad4 ASJ exome
AF:
0.0180
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00275
Gnomad4 FIN exome
AF:
0.0111
Gnomad4 NFE exome
AF:
0.0155
Gnomad4 OTH exome
AF:
0.0129
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0103
AC:
1564
AN:
152242
Hom.:
11
Cov.:
32
AF XY:
0.0104
AC XY:
776
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.00310
Gnomad4 AMR
AF:
0.0176
Gnomad4 ASJ
AF:
0.0181
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00187
Gnomad4 FIN
AF:
0.0123
Gnomad4 NFE
AF:
0.0136
Gnomad4 OTH
AF:
0.0142
Alfa
AF:
0.00638
Hom.:
1
Bravo
AF:
0.00991
Asia WGS
AF:
0.00231
AC:
8
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

OTX2-Related Syndromic Microphthalmia Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Syndromic microphthalmia type 5 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Pituitary hormone deficiency, combined, 6 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This variant is associated with the following publications: (PMID: 17541950) -
Retinal dystrophy Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Anophthalmia-microphthalmia syndrome Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
Cadd
Benign
11
Dann
Benign
0.85

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28757218; hg19: chr14-57272066; API