Genetic Variant NPEPL1:p.Leu28Pro (chr20-58692983-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_024663.4(NPEPL1):c.83T>C(p.Leu28Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NPEPL1
NM_024663.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.876

Publications

0 publications found

Variant links:

Genes affected

NPEPL1 (HGNC:16244): (aminopeptidase like 1) Predicted to enable manganese ion binding activity and metalloaminopeptidase activity. Predicted to be involved in proteolysis. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

NPEPL1 links:

STX16-NPEPL1 (HGNC:41993): (STX16-NPEPL1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring syntaxin 16 (STX16) and aminopeptidase-like 1 (NPEPL1) genes on chromosome 20. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

STX16-NPEPL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26807818).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024663.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPEPL1	NM_024663.4	MANE Select	c.83T>C	p.Leu28Pro	missense	Exon 1 of 12	NP_078939.3
NPEPL1	NM_001204872.2		c.67-754T>C		intron	N/A	NP_001191801.1	Q8NDH3-4
NPEPL1	NM_001204873.2		c.7-754T>C		intron	N/A	NP_001191802.1	Q8NDH3-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPEPL1	ENST00000356091.11	TSL:1 MANE Select	c.83T>C	p.Leu28Pro	missense	Exon 1 of 12	ENSP00000348395.6	Q8NDH3-1
NPEPL1	ENST00000525967.5	TSL:1	c.67-754T>C		intron	N/A	ENSP00000434810.1	Q8NDH3-4
STX16-NPEPL1	ENST00000530122.1	TSL:5	n.*134-754T>C		intron	N/A	ENSP00000457522.1	H3BU86

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1025772

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

494912

African (AFR)

AF:

0.00

AC:

AN:

20024

American (AMR)

AF:

0.00

AC:

AN:

15078

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13462

East Asian (EAS)

AF:

0.00

AC:

AN:

15678

South Asian (SAS)

AF:

0.00

AC:

AN:

41734

European-Finnish (FIN)

AF:

0.00

AC:

AN:

14804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2680

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

865700

Other (OTH)

AF:

0.00

AC:

AN:

36612

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.079

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.50

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.27

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

0.88

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.10

Sift

Benign

0.25

Sift4G

Benign

0.34

Polyphen

0.011

Vest4

0.52

MutPred

0.63

Loss of helix (P = 0.0068)

MVP

0.57

MPC

0.34

ClinPred

0.22

GERP RS

3.3

PromoterAI

0.026

Neutral

(source)

Varity_R

0.57

gMVP

0.80

Mutation Taster

=45/55

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over