Genetic Variant NPEPPS:p.Leu37Val (chr17-47531409-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006310.4(NPEPPS):c.109C>G(p.Leu37Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 151,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L37F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 26)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NPEPPS
NM_006310.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.09

Variant links:

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]

NPEPPS links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.066096306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPEPPS	NM_006310.4 link	c.109C>G	p.Leu37Val	missense_variant	Exon 1 of 23	ENST00000322157.9	NP_006301.3	P55786-1
NPEPPS	NM_001411130.1 link	c.109C>G	p.Leu37Val	missense_variant	Exon 1 of 24		NP_001398059.1
NPEPPS	NM_001330257.2 link	c.97C>G	p.Leu33Val	missense_variant	Exon 2 of 24		NP_001317186.1	P55786E9PLK3B7Z899
NPEPPS	XM_017025373.1 link	c.97C>G	p.Leu33Val	missense_variant	Exon 2 of 25		XP_016880862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPEPPS	ENST00000322157.9 link	c.109C>G	p.Leu37Val	missense_variant	Exon 1 of 23	1	NM_006310.4	ENSP00000320324.4		P55786-1
NPEPPS	ENST00000526247.6 link	n.97C>G		non_coding_transcript_exon_variant	Exon 2 of 8	3		ENSP00000433735.1		E9PJF9

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151426

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000682

AC:

AN:

146546

Hom.:

AF XY:

0.00

AC XY:

AN XY:

78840

show subpopulations

Gnomad AFR exome

AF:

0.000146

Gnomad AMR exome

AF:

0.00

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

Data not reliable, filtered out with message: AS_VQSR

AF:

7.16e-7

AC:

AN:

1395700

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688432

show subpopulations

Gnomad4 AFR exome

AF:

0.0000318

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151532

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74034

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.16

.;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.57

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.066

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-0.20

.;N

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.060

N;N

REVEL

Benign

0.055

Sift

Benign

0.035

D;T

Sift4G

Benign

0.12

T;T

Polyphen

0.024

B;B

Vest4

0.068

MutPred

0.31

.;Loss of helix (P = 0.028);

MVP

0.12

MPC

1.8

ClinPred

0.040

GERP RS

2.5

Varity_R

0.091

gMVP

0.52

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over