Genetic Variant OTX1:c.-180-541C>G (chr2-63050708-C-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_001199770.2(OTX1):c.-180-541C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 151,656 control chromosomes in the GnomAD database, including 17,464 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.48 ( 17464 hom., cov: 31)

Exomes 𝑓: 0.64 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

OTX1
NM_001199770.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.272

Publications

16 publications found

Variant links:

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]

OTX1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
OTX1	NM_001199770.2 link	c.-180-541C>G	intron_variant	Intron 1 of 4		NP_001186699.1	P32242
OTX1	NM_014562.4 link	c.-370C>G	upstream_gene_variant		ENST00000282549.7	NP_055377.1	P32242
OTX1	NR_130153.2 link	n.-122C>G	upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTX1	ENST00000282549.7 link	c.-370C>G		upstream_gene_variant		1	NM_014562.4	ENSP00000282549.2		P32242

Frequencies

GnomAD3 genomes

AF:

0.476

AC:

72154

AN:

151552

Hom.:

17460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.450

Gnomad AMI

AF:

0.560

Gnomad AMR

AF:

0.524

Gnomad ASJ

AF:

0.380

Gnomad EAS

AF:

0.675

Gnomad SAS

AF:

0.572

Gnomad FIN

AF:

0.396

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.476

Gnomad OTH

AF:

0.478

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.643

AC:

AN:

Hom.:

Cov.:

AF XY:

0.700

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.667

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.476

AC:

72180

AN:

151656

Hom.:

17464

Cov.:

AF XY:

0.476

AC XY:

35299

AN XY:

74098

show subpopulations

African (AFR)

AF:

0.450

AC:

18634

AN:

41400

American (AMR)

AF:

0.525

AC:

8012

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.380

AC:

1318

AN:

3464

East Asian (EAS)

AF:

0.675

AC:

3454

AN:

5114

South Asian (SAS)

AF:

0.570

AC:

2742

AN:

4812

European-Finnish (FIN)

AF:

0.396

AC:

4164

AN:

10516

Middle Eastern (MID)

AF:

0.366

AC:

107

AN:

292

European-Non Finnish (NFE)

AF:

0.476

AC:

32225

AN:

67762

Other (OTH)

AF:

0.480

AC:

1013

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1883

3765

5648

7530

9413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

652

1304

1956

2608

3260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.341

Hom.:

870

Bravo

AF:

0.484

Asia WGS

AF:

0.668

AC:

2302

AN:

3454

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

0.27

PromoterAI

0.021

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over