chr14-56805348-G-A

Variant names:

• chr14-56805348-G-A
• rs28757218
• NM_021728.4:c.97+12C>T

Variant summary

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

The ENST00000672264.2(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 ENST00000672264.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.325
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Orphanet
• pituitary hormone deficiency, combined, 6

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.79).
• BP6: Variant 14-56805348-G-A is Benign according to our data. Variant chr14-56805348-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 313422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1564 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000672264.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTX2	NM_021728.4	MANE Select	c.97+12C>T		intron	N/A	NP_068374.1
	OTX2	NM_001270525.2		c.97+12C>T		intron	N/A	NP_001257454.1
	OTX2	NM_001270523.2		c.97+12C>T		intron	N/A	NP_001257452.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTX2	ENST00000672264.2	MANE Select	c.97+12C>T		intron	N/A	ENSP00000500115.1
	OTX2	ENST00000554845.2	TSL:1	c.97+12C>T		intron	N/A	ENSP00000451357.2
	OTX2	ENST00000339475.10	TSL:1	c.97+12C>T		intron	N/A	ENSP00000343819.5

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1565 AN: 152124 Hom.: 11 Cov.: 32

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

GnomAD2 exomes AF: 0.0102 AC: 2554 AN: 250260 AF XY: 0.0101

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 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

African (AFR) AF: 0.00243 AC: 80 AN: 32926

American (AMR) AF: 0.00788 AC: 352 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 469 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.00275 AC: 235 AN: 85606

European-Finnish (FIN) AF: 0.0111 AC: 590 AN: 53370

Middle Eastern (MID) AF: 0.00356 AC: 20 AN: 5616

European-Non Finnish (NFE) AF: 0.0155 AC: 16849 AN: 1084058

Other (OTH) AF: 0.0129 AC: 764 AN: 59364

GnomAD4 genome AF: 0.0103 AC: 1564 AN: 152242 Hom.: 11 Cov.: 32 AF XY: 0.0104 AC XY: 776 AN XY: 74442

African (AFR) AF: 0.00310 AC: 129 AN: 41564

American (AMR) AF: 0.0176 AC: 270 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 63 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.0123 AC: 131 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0136 AC: 927 AN: 68010

Other (OTH) AF: 0.0142 AC: 30 AN: 2110

Alfa AF: 0.00638 Hom.: 1

Bravo AF: 0.00991

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Anophthalmia-microphthalmia syndrome (1)
-	-	1	OTX2-Related Syndromic Microphthalmia (1)
-	-	1	Pituitary hormone deficiency, combined, 6 (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Syndromic microphthalmia type 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		-0.33
PromoterAI		0.010	Neutral
Mutation Taster		=100/0	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: rs28757218; hg19: chr14-57272066;