chr14-56802170-G-A

Position:

chr14-56802170-G-A

Variant summary

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

The NM_021728.4(OTX2):c.459C>T(p.Ser153Ser) variant causes a synonymous change. The variant allele was found at a frequency of 0.00165 in 1,614,094 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 26 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 15 hom. )

Consequence

OTX2
NM_021728.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 6.54

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]

OTX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 14-56802170-G-A is Benign according to our data. Variant chr14-56802170-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 313417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-56802170-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00882 (1343/152280) while in subpopulation AFR AF= 0.0311 (1292/41536). AF 95% confidence interval is 0.0297. There are 26 homozygotes in gnomad4. There are 616 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1343 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTX2	NM_021728.4 link	c.459C>T	p.Ser153Ser	synonymous_variant	5/5	ENST00000672264.2	NP_068374.1	P32243-2F1T0D1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTX2	ENST00000672264.2 link	c.459C>T	p.Ser153Ser	synonymous_variant	5/5		NM_021728.4	ENSP00000500115.1		P32243-2

Frequencies

GnomAD3 genomes

AF:

0.00879

AC:

1337

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0311

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

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:

0.0000294

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00222

AC:

558

AN:

251380

Hom.:

AF XY:

0.00156

AC XY:

212

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.0308

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000900

AC:

1316

AN:

1461814

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

556

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.0315

Gnomad4 AMR exome

AF:

0.00161

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.00214

GnomAD4 genome

AF:

0.00882

AC:

1343

AN:

152280

Hom.:

Cov.:

AF XY:

0.00827

AC XY:

616

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0311

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00428

Hom.:

Bravo

AF:

0.0101

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

OTX2-Related Syndromic Microphthalmia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Syndromic microphthalmia type 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This 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 submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Syndromic microphthalmia type 5;C3151440:Pituitary hormone deficiency, combined, 6

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 25, 2021

- -

Syndromic Microphthalmia, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Anophthalmia-microphthalmia syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.58

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over