20-58692959-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024663.4(NPEPL1):​c.59G>A​(p.Arg20Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000192 in 1,040,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: NPEPL1 NM_024663.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1571149).

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.59G>A	p.Arg20Gln	missense	Exon 1 of 12	NP_078939.3
	NPEPL1	NM_001204872.2		c.67-778G>A		intron	N/A	NP_001191801.1	Q8NDH3-4
	NPEPL1	NM_001204873.2		c.7-778G>A		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.59G>A	p.Arg20Gln	missense	Exon 1 of 12	ENSP00000348395.6	Q8NDH3-1
	NPEPL1	ENST00000525967.5	TSL:1	c.67-778G>A		intron	N/A	ENSP00000434810.1	Q8NDH3-4
	STX16-NPEPL1	ENST00000530122.1	TSL:5	n.*134-778G>A		intron	N/A	ENSP00000457522.1	H3BU86

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000192 AC: 2 AN: 1040116 Hom.: 0 Cov.: 32 AF XY: 0.00000198 AC XY: 1 AN XY: 504848

⚠️ 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: 20050

American (AMR) AF: 0.00 AC: 0 AN: 14890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13564

East Asian (EAS) AF: 0.00 AC: 0 AN: 15908

South Asian (SAS) AF: 0.0000220 AC: 1 AN: 45480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2988

European-Non Finnish (NFE) AF: 0.00000114 AC: 1 AN: 874670

Other (OTH) AF: 0.00 AC: 0 AN: 37128

⚠️ 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.15
Sift	Benign	0.28	T
Sift4G	Benign	0.43	T
Polyphen		0.59	P
Vest4		0.30
MutPred		0.15		Gain of helix (P = 0.0854)
MVP		0.24
MPC		0.25
ClinPred		0.36	T
GERP RS		1.2
PromoterAI		0.034	Neutral
Varity_R		0.087
gMVP		0.57
Mutation Taster		=66/34	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

dbSNP: rs2084385144; hg19: chr20-57268015;