chr9-94760546-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001193329.3(AOPEP):​c.763C>T​(p.Arg255*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,560,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

AOPEP
NM_001193329.3 stop_gained

Scores

2
4
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 2.05

Publications

1 publications found
Variant links:
Genes affected
AOPEP (HGNC:1361): (aminopeptidase O (putative)) This gene encodes a member of the M1 zinc aminopeptidase family. The encoded protein is a zinc-dependent metallopeptidase that catalyzes the removal of an amino acid from the amino terminus of a protein or peptide. This protein may play a role in the generation of angiotensin IV. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-94760546-C-T is Pathogenic according to our data. Variant chr9-94760546-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1319961.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AOPEPNM_001193329.3 linkc.763C>T p.Arg255* stop_gained Exon 2 of 17 ENST00000375315.8 NP_001180258.1 Q8N6M6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AOPEPENST00000375315.8 linkc.763C>T p.Arg255* stop_gained Exon 2 of 17 1 NM_001193329.3 ENSP00000364464.2 Q8N6M6-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152100
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000415
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000300
AC:
6
AN:
200132
AF XY:
0.0000283
show subpopulations
Gnomad AFR exome
AF:
0.0000639
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000316
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000376
AC:
53
AN:
1408316
Hom.:
0
Cov.:
31
AF XY:
0.0000474
AC XY:
33
AN XY:
695788
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31498
American (AMR)
AF:
0.00
AC:
0
AN:
35768
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
22206
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39358
South Asian (SAS)
AF:
0.0000528
AC:
4
AN:
75796
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51458
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5478
European-Non Finnish (NFE)
AF:
0.0000432
AC:
47
AN:
1088774
Other (OTH)
AF:
0.0000345
AC:
2
AN:
57980
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.462
Heterozygous variant carriers
0
3
7
10
14
17
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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
AF:
0.0000329
AC:
5
AN:
152100
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74302
show subpopulations
African (AFR)
AF:
0.0000242
AC:
1
AN:
41406
American (AMR)
AF:
0.00
AC:
0
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.000415
AC:
2
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.515
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Dystonia 31 Pathogenic:2
Jan 28, 2022
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Oct 17, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
36
DANN
Uncertain
1.0
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.82
D
PhyloP100
2.1
Vest4
0.36
GERP RS
3.8
PromoterAI
-0.032
Neutral
Mutation Taster
=24/176
disease causing (fs/PTC)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs779393035; hg19: chr9-97522828; API