chr17-47531554-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_006310.4(NPEPPS):c.254A>G(p.Gln85Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000025 in 1,600,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 27)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
NPEPPS
NM_006310.4 missense, splice_region
NM_006310.4 missense, splice_region
Scores
3
14
Splicing: ADA: 0.9986
2
Clinical Significance
Conservation
PhyloP100: 4.09
Genes affected
NPEPPS (HGNC:7900): (aminopeptidase puromycin sensitive) This gene encodes the puromycin-sensitive aminopeptidase, a zinc metallopeptidase which hydrolyzes amino acids from the N-terminus of its substrate. The protein has been localized to both the cytoplasm and to cellular membranes. This enzyme degrades enkaphalins in the brain, and studies in mouse suggest that it is involved in proteolytic events regulating the cell cycle. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, NPEPPS
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPEPPS | NM_006310.4 | c.254A>G | p.Gln85Arg | missense_variant, splice_region_variant | 1/23 | ENST00000322157.9 | |
NPEPPS | NM_001411130.1 | c.254A>G | p.Gln85Arg | missense_variant, splice_region_variant | 1/24 | ||
NPEPPS | NM_001330257.2 | c.242A>G | p.Gln81Arg | missense_variant, splice_region_variant | 2/24 | ||
NPEPPS | XM_017025373.1 | c.242A>G | p.Gln81Arg | missense_variant, splice_region_variant | 2/25 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPEPPS | ENST00000322157.9 | c.254A>G | p.Gln85Arg | missense_variant, splice_region_variant | 1/23 | 1 | NM_006310.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151634Hom.: 0 Cov.: 27
GnomAD3 genomes
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GnomAD4 exome AF: 0.00000207 AC: 3AN: 1449250Hom.: 0 Cov.: 33 AF XY: 0.00000278 AC XY: 2AN XY: 720202
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GnomAD4 genome ? AF: 0.00000659 AC: 1AN: 151634Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 74040
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 16, 2023 | The c.254A>G (p.Q85R) alteration is located in exon 1 (coding exon 1) of the NPEPPS gene. This alteration results from a A to G substitution at nucleotide position 254, causing the glutamine (Q) at amino acid position 85 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
0.0
.;B;B
Vest4
0.26, 0.23
MutPred
0.46
.;.;Gain of methylation at Q85 (P = 0.0501);
MVP
MPC
1.9
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at