6-105323714-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002726.5(PREP):​c.1268G>A​(p.Arg423Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,786 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 (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PREP
NM_002726.5 missense

Scores

5
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57
Variant links:
Genes affected
PREP (HGNC:9358): (prolyl endopeptidase) The protein encoded by this gene is a cytosolic prolyl endopeptidase that cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. Prolyl endopeptidases have been reported to be involved in the maturation and degradation of peptide hormones and neuropeptides. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PREPNM_002726.5 linkc.1268G>A p.Arg423Gln missense_variant Exon 10 of 15 ENST00000652536.2 NP_002717.3 P48147B2RAH7
PREPXM_011535925.4 linkc.1268G>A p.Arg423Gln missense_variant Exon 10 of 11 XP_011534227.1
PREPXM_005267044.4 linkc.1268G>A p.Arg423Gln missense_variant Exon 10 of 11 XP_005267101.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PREPENST00000652536.2 linkc.1268G>A p.Arg423Gln missense_variant Exon 10 of 15 NM_002726.5 ENSP00000499089.1 P48147
PREPENST00000369110.8 linkc.1070G>A p.Arg357Gln missense_variant Exon 12 of 17 1 ENSP00000358106.4 A0A499FJL1
PREPENST00000448705.1 linkc.53G>A p.Arg18Gln missense_variant Exon 1 of 2 2 ENSP00000401796.1 H0Y5Y0

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152194
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251266
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135782
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461474
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727084
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152312
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000499
Hom.:
0
Bravo
AF:
0.0000567
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000412
AC:
5

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 19, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1268G>A (p.R423Q) alteration is located in exon 10 (coding exon 10) of the PREP gene. This alteration results from a G to A substitution at nucleotide position 1268, causing the arginine (R) at amino acid position 423 to be replaced by a glutamine (Q). 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
Benign
0.20
BayesDel_addAF
Benign
-0.038
T
BayesDel_noAF
Uncertain
-0.070
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.37
T
Eigen
Uncertain
0.67
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D
M_CAP
Benign
0.020
T
MetaRNN
Pathogenic
0.74
D
MetaSVM
Benign
-1.1
T
MutationAssessor
Pathogenic
3.0
M
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-2.6
D
REVEL
Uncertain
0.29
Sift
Uncertain
0.021
D
Sift4G
Uncertain
0.025
D
Polyphen
0.99
D
Vest4
0.92
MVP
0.24
MPC
0.63
ClinPred
0.76
D
GERP RS
5.9
Varity_R
0.70

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: rs141737006; hg19: chr6-105771589; COSMIC: COSV64869888; API