14-56802170-G-A

Variant names:

• chr14-56802170-G-A
• rs34537598
• NM_021728.4:c.459C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.54
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• syndromic microphthalmia type 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• pituitary hormone deficiency, combined, 6

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• combined pituitary hormone deficiencies, genetic form

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated anophthalmia-microphthalmia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• patterned macular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• septooptic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 313417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1343 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021728.4. 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
	OTX2	NM_021728.4	MANE Select	c.459C>T	p.Ser153Ser	synonymous	Exon 5 of 5	NP_068374.1	F1T0D1
	OTX2	NM_001270525.2		c.459C>T	p.Ser153Ser	synonymous	Exon 3 of 3	NP_001257454.1	F1T0D1
	OTX2	NM_001270523.2		c.435C>T	p.Ser145Ser	synonymous	Exon 5 of 5	NP_001257452.1	P32243-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTX2	ENST00000672264.2	MANE Select	c.459C>T	p.Ser153Ser	synonymous	Exon 5 of 5	ENSP00000500115.1	P32243-2
	OTX2	ENST00000554845.2	TSL:1	c.459C>T	p.Ser153Ser	synonymous	Exon 3 of 3	ENSP00000451357.2	P32243-2
	OTX2	ENST00000339475.10	TSL:1	c.435C>T	p.Ser145Ser	synonymous	Exon 5 of 5	ENSP00000343819.5	P32243-1

Frequencies

GnomAD3 genomes AF: 0.00879 AC: 1337 AN: 152162 Hom.: 26 Cov.: 32

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

GnomAD2 exomes AF: 0.00222 AC: 558 AN: 251380 AF XY: 0.00156

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 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.: 15 Cov.: 32 AF XY: 0.000765 AC XY: 556 AN XY: 727186

African (AFR) AF: 0.0315 AC: 1056 AN: 33480

American (AMR) AF: 0.00161 AC: 72 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111940

Other (OTH) AF: 0.00214 AC: 129 AN: 60396

GnomAD4 genome AF: 0.00882 AC: 1343 AN: 152280 Hom.: 26 Cov.: 32 AF XY: 0.00827 AC XY: 616 AN XY: 74478

African (AFR) AF: 0.0311 AC: 1292 AN: 41536

American (AMR) AF: 0.00255 AC: 39 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

Alfa AF: 0.00434 Hom.: 11

Bravo AF: 0.0101

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Anophthalmia-microphthalmia syndrome (1)
-	-	1	not provided (1)
-	-	1	OTX2-Related Syndromic Microphthalmia (1)
-	-	1	Pituitary hormone deficiency, combined, 6 (1)
-	-	1	Syndromic microphthalmia type 5 (1)
-	-	1	Syndromic microphthalmia type 5;C3151440:Pituitary hormone deficiency, combined, 6 (1)
-	-	1	Syndromic Microphthalmia, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	11
DANN	Benign	0.58
PhyloP100		6.5
Mutation Taster		=52/36	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: rs34537598; hg19: chr14-57268888;