20-58693012-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024663.4(NPEPL1):c.112C>T(p.His38Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,112,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000052 ( 0 hom. )

Consequence

NPEPL1
NM_024663.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.889

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14921755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPEPL1	NM_024663.4 link	c.112C>T	p.His38Tyr	missense_variant	Exon 1 of 12	ENST00000356091.11	NP_078939.3	Q8NDH3-1
NPEPL1	NM_001204872.2 link	c.67-725C>T		intron_variant	Intron 2 of 12		NP_001191801.1	Q8NDH3-4
NPEPL1	NM_001204873.2 link	c.7-725C>T		intron_variant	Intron 2 of 12		NP_001191802.1	Q8NDH3-5
STX16-NPEPL1	NR_037945.1 link	n.2037-725C>T		intron_variant	Intron 11 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPEPL1	ENST00000356091.11 link	c.112C>T	p.His38Tyr	missense_variant	Exon 1 of 12	1	NM_024663.4	ENSP00000348395.6		Q8NDH3-1
STX16-NPEPL1	ENST00000530122.1 link	n.*134-725C>T		intron_variant	Intron 11 of 22	5		ENSP00000457522.1		H3BU86

Frequencies

GnomAD3 genomes

AF:

0.000115

AC:

AN:

147212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000390

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000675

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

GnomAD4 exome

AF:

0.00000518

AC:

AN:

965430

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

459468

show subpopulations

Gnomad4 AFR exome

AF:

0.000215

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:

0.00000120

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000115

AC:

AN:

147212

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

71612

show subpopulations

Gnomad4 AFR

AF:

0.000390

Gnomad4 AMR

AF:

0.0000675

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

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000140

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.112C>T (p.H38Y) alteration is located in exon 1 (coding exon 1) of the NPEPL1 gene. This alteration results from a C to T substitution at nucleotide position 112, causing the histidine (H) at amino acid position 38 to be replaced by a tyrosine (Y). 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

0.083

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.054

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.61

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.2

REVEL

Benign

0.053

Sift

Benign

0.073

Sift4G

Benign

0.083

Polyphen

0.14

Vest4

0.19

MutPred

0.43

Loss of disorder (P = 0.0377);

MVP

0.30

MPC

0.25

ClinPred

0.31

GERP RS

3.4

Varity_R

0.16

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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