NM_024663.4:c.169A>G

Variant names:

• chr20-58693755-A-G
• rs2084402959
• NM_024663.4:c.169A>G

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.169A>G​(p.Ser57Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPEPL1 NM_024663.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.426
• 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=0.10383609).

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.169A>G	p.Ser57Gly	missense	Exon 2 of 12	NP_078939.3
	NPEPL1	NM_001204872.2		c.85A>G	p.Ser29Gly	missense	Exon 3 of 13	NP_001191801.1	Q8NDH3-4
	NPEPL1	NM_001204873.2		c.25A>G	p.Ser9Gly	missense	Exon 3 of 13	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.169A>G	p.Ser57Gly	missense	Exon 2 of 12	ENSP00000348395.6	Q8NDH3-1
	NPEPL1	ENST00000525967.5	TSL:1	c.85A>G	p.Ser29Gly	missense	Exon 3 of 13	ENSP00000434810.1	Q8NDH3-4
	NPEPL1	ENST00000529976.5	TSL:1	n.587A>G		non_coding_transcript_exon	Exon 1 of 7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000478

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456758 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723784

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.0000225 AC: 1 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108176

Other (OTH) AF: 0.0000166 AC: 1 AN: 60142

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

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	Benign	0.059
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.43
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.016
Sift	Benign	0.20	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.32		Loss of glycosylation at S57 (P = 0.0764)
MVP		0.27
MPC		0.19
ClinPred		0.13	T
GERP RS		1.2
Varity_R		0.057
gMVP		0.27
Mutation Taster		=93/7	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: rs2084402959; hg19: chr20-57268811;