20-58692959-G-C

Variant names:

• chr20-58692959-G-C
• rs2084385144
• NM_024663.4:c.59G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024663.4(NPEPL1):​c.59G>C​(p.Arg20Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.65

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28508908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPEPL1	NM_024663.4	c.59G>C	p.Arg20Pro	missense_variant	Exon 1 of 12	ENST00000356091.11	NP_078939.3
NPEPL1	NM_001204872.2	c.67-778G>C		intron_variant	Intron 2 of 12		NP_001191801.1
NPEPL1	NM_001204873.2	c.7-778G>C		intron_variant	Intron 2 of 12		NP_001191802.1
STX16-NPEPL1	NR_037945.1	n.2037-778G>C		intron_variant	Intron 11 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPEPL1	ENST00000356091.11	c.59G>C	p.Arg20Pro	missense_variant	Exon 1 of 12	1	NM_024663.4	ENSP00000348395.6
STX16-NPEPL1	ENST00000530122.1	n.*134-778G>C		intron_variant	Intron 11 of 22	5		ENSP00000457522.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1040116 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 504848

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.59G>C (p.R20P) alteration is located in exon 1 (coding exon 1) of the NPEPL1 gene. This alteration results from a G to C substitution at nucleotide position 59, causing the arginine (R) at amino acid position 20 to be replaced by a proline (P). 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	0.84
BayesDel_addAF	Benign	-0.0030	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.22
Sift	Benign	0.069	T
Sift4G	Benign	0.16	T
Polyphen		0.97	D
Vest4		0.32
MutPred		0.28		Gain of glycosylation at R20 (P = 0.0075);
MVP		0.45
MPC		0.64
ClinPred		0.70	D
GERP RS		1.2
Varity_R		0.48
gMVP		0.77

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

Other links and lift over

dbSNP: rs2084385144; hg19: chr20-57268015;