Variant 17-47531409-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_006310.4(NPEPPS):c.109C>T(p.Leu37Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000769 in 1,547,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

NPEPPS
NM_006310.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2

Missense variant where missense usually causes diseases, NPEPPS

BP4

Computational evidence support a benign effect (MetaRNN=0.05392331).

BS2

High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NPEPPS	NM_006310.4 linkuse as main transcript	c.109C>T	p.Leu37Phe	missense_variant	1/23	ENST00000322157.9
NPEPPS	NM_001411130.1 linkuse as main transcript	c.109C>T	p.Leu37Phe	missense_variant	1/24
NPEPPS	NM_001330257.2 linkuse as main transcript	c.97C>T	p.Leu33Phe	missense_variant	2/24
NPEPPS	XM_017025373.1 linkuse as main transcript	c.97C>T	p.Leu33Phe	missense_variant	2/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPEPPS	ENST00000322157.9 linkuse as main transcript	c.109C>T	p.Leu37Phe	missense_variant	1/23	1	NM_006310.4	P1	P55786-1

Frequencies

GnomAD3 genomes

AF:

0.0000726

AC:

AN:

151426

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000109

AC:

AN:

146546

Hom.:

AF XY:

0.0000761

AC XY:

AN XY:

78840

show subpopulations

Gnomad AFR exome

AF:

0.000146

Gnomad AMR exome

AF:

0.000287

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:

0.000129

Gnomad OTH exome

AF:

0.000236

GnomAD4 exome

AF:

0.0000774

AC:

108

AN:

1395700

Hom.:

Cov.:

AF XY:

0.0000697

AC XY:

AN XY:

688432

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000252

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000807

Gnomad4 OTH exome

AF:

0.000173

GnomAD4 genome

AF:

0.0000726

AC:

AN:

151532

Hom.:

Cov.:

AF XY:

0.0000810

AC XY:

AN XY:

74034

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000253

AC:

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

Jul 19, 2022

The c.109C>T (p.L37F) alteration is located in exon 1 (coding exon 1) of the NPEPPS gene. This alteration results from a C to T substitution at nucleotide position 109, causing the leucine (L) at amino acid position 37 to be replaced by a phenylalanine (F). 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

0.079

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.68

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.56

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.054

T;T

MetaSVM

Benign

-0.86

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.29

N;N

REVEL

Benign

0.068

Sift

Benign

0.030

D;T

Sift4G

Benign

0.26

T;T

Polyphen

0.0

B;B

Vest4

0.066

MVP

0.082

MPC

1.9

ClinPred

0.026

GERP RS

2.5

Varity_R

0.070

gMVP

0.49

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over