rs751090870

Variant names:

• chr20-58693897-C-A
• rs751090870
• NM_024663.4:c.311C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-58693897-C-A
• chr20-58693897-C-T

Variant summary

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

The NM_024663.4(NPEPL1):​c.311C>A​(p.Pro104Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,420 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P104L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPEPL1 NM_024663.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51
• 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.311C>A	p.Pro104Gln	missense	Exon 2 of 12	NP_078939.3
	NPEPL1	NM_001204872.2		c.227C>A	p.Pro76Gln	missense	Exon 3 of 13	NP_001191801.1	Q8NDH3-4
	NPEPL1	NM_001204873.2		c.167C>A	p.Pro56Gln	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.311C>A	p.Pro104Gln	missense	Exon 2 of 12	ENSP00000348395.6	Q8NDH3-1
	NPEPL1	ENST00000525967.5	TSL:1	c.227C>A	p.Pro76Gln	missense	Exon 3 of 13	ENSP00000434810.1	Q8NDH3-4
	NPEPL1	ENST00000529976.5	TSL:1	n.729C>A		non_coding_transcript_exon	Exon 1 of 7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457420 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 724710

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39470

South Asian (SAS) AF: 0.00 AC: 0 AN: 85928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109888

Other (OTH) AF: 0.00 AC: 0 AN: 60182

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.052	T
Eigen	Benign	0.062
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.089
Sift	Benign	0.62	T
Sift4G	Benign	0.58	T
Polyphen		0.0090	B
Vest4		0.65
MutPred		0.42		Gain of MoRF binding (P = 0.0393)
MVP		0.52
MPC		0.22
ClinPred		0.92	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.61
Mutation Taster		=41/59	disease causing

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: rs751090870; hg19: chr20-57268953;