rs193921074
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_017712.4(PGPEP1):c.434G>A(p.Gly145Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,212 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 Uncertain significance (no stars).
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 31)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PGPEP1
NM_017712.4 missense
NM_017712.4 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 9.20
Publications
0 publications found
Genes affected
PGPEP1 (HGNC:13568): (pyroglutamyl-peptidase I) The gene encodes a cysteine protease and member of the peptidase C15 family of proteins. The encoded protein cleaves amino terminal pyroglutamate residues from protein substrates including thyrotropin-releasing hormone and other neuropeptides. Expression of this gene may be downregulated in colorectal cancer, while activity of the encoded protein may be negatively correlated with cancer progression in colorectal cancer patients. Activity of the encoded protease may also be altered in other disease states including in liver cirrhosis, which is associated with reduced protease activity, and in necrozoospermia, which is associated with elevated protease activity. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 152126Hom.: 0 Cov.: 31
GnomAD3 genomes
AF:
AC:
0
AN:
152126
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 6.91e-7 AC: 1AN: 1446212Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 718440 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1446212
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
718440
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33058
American (AMR)
AF:
AC:
0
AN:
42758
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25836
East Asian (EAS)
AF:
AC:
0
AN:
38818
South Asian (SAS)
AF:
AC:
0
AN:
84118
European-Finnish (FIN)
AF:
AC:
0
AN:
51970
Middle Eastern (MID)
AF:
AC:
0
AN:
5750
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1104046
Other (OTH)
AF:
AC:
1
AN:
59858
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
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
Exome 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
GnomAD4 genome 0.00 AC: 0AN: 152126Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74286
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
152126
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
74286
African (AFR)
AF:
AC:
0
AN:
41420
American (AMR)
AF:
AC:
0
AN:
15254
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5190
South Asian (SAS)
AF:
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68030
Other (OTH)
AF:
AC:
0
AN:
2090
Alfa
AF:
Hom.:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Prostate cancer Uncertain:1
-
Science for Life laboratory, Karolinska Institutet
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;T;T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;T;T;D;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;.;.
PhyloP100
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;D;.
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;.;.;.;.
Vest4
MutPred
Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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