chr5-77630546-C-T

Variant summary

Our verdict is Likely benign. Variant got -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

2
10
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.52
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OTPNM_032109.3 linkc.696G>A p.Met232Ile missense_variant Exon 3 of 3 ENST00000306422.5 NP_115485.1 Q5XKR4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OTPENST00000306422.5 linkc.696G>A p.Met232Ile missense_variant Exon 3 of 3 1 NM_032109.3 ENSP00000302814.3 Q5XKR4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000227
AC:
4
AN:
176434
Hom.:
0
AF XY:
0.0000308
AC XY:
3
AN XY:
97404
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 SAS 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:
6
AN:
1425618
Hom.:
0
Cov.:
30
AF XY:
0.00000566
AC XY:
4
AN XY:
706666
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000740
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000182
Gnomad4 OTH exome
AF:
0.0000169
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756
ExAC
AF:
0.00000872
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 01, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.696G>A (p.M232I) alteration is located in exon 3 (coding exon 3) of the OTP gene. This alteration results from a G to A substitution at nucleotide position 696, causing the methionine (M) at amino acid position 232 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Benign
-0.018
T
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.13
T
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.88
D
M_CAP
Pathogenic
0.89
D
MetaRNN
Uncertain
0.51
D
MetaSVM
Uncertain
0.24
D
MutationAssessor
Benign
1.6
L
PrimateAI
Pathogenic
0.91
D
PROVEAN
Benign
-0.63
N
REVEL
Uncertain
0.43
Sift
Benign
0.13
T
Sift4G
Benign
0.20
T
Polyphen
0.85
P
Vest4
0.48
MutPred
0.24
Gain of glycosylation at S235 (P = 0.0921);
MVP
0.74
MPC
0.97
ClinPred
0.76
D
GERP RS
3.6
Varity_R
0.38
gMVP
0.73

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.

Other links and lift over

dbSNP: rs780446029; hg19: chr5-76926371; API