Genetic Variant NPEPL1:p.Arg97Gly (chr20-58693875-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024663.4(NPEPL1):c.289C>G(p.Arg97Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,460,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

NPEPL1
NM_024663.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.67

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPEPL1	NM_024663.4 link	c.289C>G	p.Arg97Gly	missense_variant	Exon 2 of 12	ENST00000356091.11	NP_078939.3	Q8NDH3-1
NPEPL1	NM_001204872.2 link	c.205C>G	p.Arg69Gly	missense_variant	Exon 3 of 13		NP_001191801.1	Q8NDH3-4
NPEPL1	NM_001204873.2 link	c.145C>G	p.Arg49Gly	missense_variant	Exon 3 of 13		NP_001191802.1	Q8NDH3-5
STX16-NPEPL1	NR_037945.1 link	n.2175C>G		non_coding_transcript_exon_variant	Exon 12 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPEPL1	ENST00000356091.11 link	c.289C>G	p.Arg97Gly	missense_variant	Exon 2 of 12	1	NM_024663.4	ENSP00000348395.6	Q8NDH3-1
STX16-NPEPL1	ENST00000530122.1 link	n.*272C>G		non_coding_transcript_exon_variant	Exon 12 of 23	5		ENSP00000457522.1	H3BU86
STX16-NPEPL1	ENST00000530122.1 link	n.*272C>G		3_prime_UTR_variant	Exon 12 of 23	5		ENSP00000457522.1	H3BU86

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

243152

Hom.:

AF XY:

0.0000226

AC XY:

AN XY:

132558

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000276

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1460720

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726642

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.289C>G (p.R97G) alteration is located in exon 2 (coding exon 2) of the NPEPL1 gene. This alteration results from a C to G substitution at nucleotide position 289, causing the arginine (R) at amino acid position 97 to be replaced by a glycine (G). 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

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

.;.;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.056

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

.;.;M

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.014

D;D;D

Sift4G

Uncertain

0.033

D;D;D

Polyphen

0.91

.;.;P

Vest4

0.81

MutPred

0.49

.;.;Loss of MoRF binding (P = 0.0325);

MVP

0.52

MPC

0.29

ClinPred

0.95

GERP RS

-3.8

Varity_R

0.77

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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