Genetic Variant NM_032109.3:c.696G>A (chr5-77630546-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_032109.3(OTP):c.696G>A(p.Met232Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000421 in 1,425,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M232V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

OTP
NM_032109.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.52

Publications

1 publications found

Variant links:

Genes affected

OTP (HGNC:8518): (orthopedia homeobox) This gene encodes a member of the homeodomain (HD) family. HD family proteins are helix-turn-helix transcription factors that play key roles in the specification of cell fates. This protein may function during brain development. [provided by RefSeq, Jul 2008]

OTP links:

OTP-AS1 (HGNC:):

OTP-AS1 links:

OTP-AS1 (HGNC:58154):

OTP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032109.3. 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
	OTP	NM_032109.3	MANE Select	c.696G>A	p.Met232Ile	missense	Exon 3 of 3	NP_115485.1	Q5XKR4
	OTP-AS1	NR_198942.1		n.91+785C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTP	ENST00000306422.5	TSL:1 MANE Select	c.696G>A	p.Met232Ile	missense	Exon 3 of 3	ENSP00000302814.3	Q5XKR4
	OTP-AS1	ENST00000851058.1		n.91+785C>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000227

AC:

AN:

176434

AF XY:

0.0000308

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000138

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000421

AC:

AN:

1425618

Hom.:

Cov.:

AF XY:

0.00000566

AC XY:

AN XY:

706666

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32660

American (AMR)

AF:

0.0000740

AC:

AN:

40522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25430

East Asian (EAS)

AF:

0.00

AC:

AN:

38100

South Asian (SAS)

AF:

0.00

AC:

AN:

82252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1097470

Other (OTH)

AF:

0.0000169

AC:

AN:

59078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000872

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.89

MetaRNN

Uncertain

0.51

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

1.6

PhyloP100

4.5

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.63

REVEL

Uncertain

0.43

Sift

Benign

0.13

Sift4G

Benign

0.20

Polyphen

0.85

Vest4

0.48

MutPred

0.24

Gain of glycosylation at S235 (P = 0.0921)

MVP

0.74

MPC

0.97

ClinPred

0.76

GERP RS

3.6

Varity_R

0.38

gMVP

0.73

Mutation Taster

=48/52

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over