20-58693036-C-T

Variant names:

• chr20-58693036-C-T
• NM_024663.4:c.136C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024663.4(NPEPL1):​c.136C>T​(p.Arg46Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000111 in 904,900 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R46Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: NPEPL1 NM_024663.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPEPL1	NM_024663.4	MANE Select	c.136C>T	p.Arg46Trp	missense	Exon 1 of 12	NP_078939.3
	NPEPL1	NM_001204872.2		c.67-701C>T		intron	N/A	NP_001191801.1	Q8NDH3-4
	NPEPL1	NM_001204873.2		c.7-701C>T		intron	N/A	NP_001191802.1	Q8NDH3-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPEPL1	ENST00000356091.11	TSL:1 MANE Select	c.136C>T	p.Arg46Trp	missense	Exon 1 of 12	ENSP00000348395.6	Q8NDH3-1
	NPEPL1	ENST00000525967.5	TSL:1	c.67-701C>T		intron	N/A	ENSP00000434810.1	Q8NDH3-4
	STX16-NPEPL1	ENST00000530122.1	TSL:5	n.*134-701C>T		intron	N/A	ENSP00000457522.1	H3BU86

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000111 AC: 1 AN: 904900 Hom.: 0 Cov.: 32 AF XY: 0.00000235 AC XY: 1 AN XY: 424664

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 17192

American (AMR) AF: 0.00 AC: 0 AN: 3656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7376

East Asian (EAS) AF: 0.00 AC: 0 AN: 10652

South Asian (SAS) AF: 0.00 AC: 0 AN: 21942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1974

European-Non Finnish (NFE) AF: 0.00000124 AC: 1 AN: 804154

Other (OTH) AF: 0.00 AC: 0 AN: 31002

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.022
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.18
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.24
MutPred		0.46		Loss of helix (P = 0.0167)
MVP		0.61
MPC		0.65
ClinPred		0.96	D
GERP RS		2.4
PromoterAI		0.014	Neutral
Varity_R		0.30
gMVP		0.56
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

hg19: chr20-57268092;