rs25653

Positions:

• chr15-89806327-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001150.3(ANPEP):​c.257G>A​(p.Arg86Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 1,613,860 control chromosomes in the GnomAD database, including 233,638 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.59 (29065 hom., cov: 32)
  • Exomes 𝑓: 0.52 (204573 hom.)
• Consequence: ANPEP NM_001150.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.409

Genes affected

ANPEP (HGNC:500): (alanyl aminopeptidase, membrane) Aminopeptidase N is located in the small-intestinal and renal microvillar membrane, and also in other plasma membranes. In the small intestine aminopeptidase N plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. Its function in proximal tubular epithelial cells and other cell types is less clear. The large extracellular carboxyterminal domain contains a pentapeptide consensus sequence characteristic of members of the zinc-binding metalloproteinase superfamily. Sequence comparisons with known enzymes of this class showed that CD13 and aminopeptidase N are identical. The latter enzyme was thought to be involved in the metabolism of regulatory peptides by diverse cell types, including small intestinal and renal tubular epithelial cells, macrophages, granulocytes, and synaptic membranes from the CNS. This membrane-bound zinc metalloprotease is known to serve as a receptor for the HCoV-229E alphacoronavirus as well as other non-human coronaviruses. This gene has also been shown to promote angiogenesis, tumor growth, and metastasis and defects in this gene are associated with various types of leukemia and lymphoma. [provided by RefSeq, Apr 2020]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.6368644E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.852 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANPEP	NM_001150.3	c.257G>A	p.Arg86Gln	missense_variant	2/21	ENST00000300060.7	NP_001141.2
ANPEP	NM_001381923.1	c.257G>A	p.Arg86Gln	missense_variant	2/21		NP_001368852.1
ANPEP	NM_001381924.1	c.257G>A	p.Arg86Gln	missense_variant	1/20		NP_001368853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANPEP	ENST00000300060.7	c.257G>A	p.Arg86Gln	missense_variant	2/21	1	NM_001150.3	ENSP00000300060	P1
ANPEP	ENST00000559874.2	c.257G>A	p.Arg86Gln	missense_variant	2/21	3		ENSP00000452934	P1
ANPEP	ENST00000560137.2	c.257G>A	p.Arg86Gln	missense_variant	2/21	3		ENSP00000453413	P1
ANPEP	ENST00000679248.1	c.257G>A	p.Arg86Gln	missense_variant	3/22			ENSP00000502886	P1

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90295 AN: 151868 Hom.: 29013 Cov.: 32

Gnomad AFR AF: 0.859

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.526

Gnomad OTH AF: 0.544

GnomAD3 exomes AF: 0.495 AC: 124477 AN: 251446 Hom.: 33058 AF XY: 0.494 AC XY: 67118 AN XY: 135890

Gnomad AFR exome AF: 0.864

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.522

Gnomad EAS exome AF: 0.467

Gnomad SAS exome AF: 0.446

Gnomad FIN exome AF: 0.433

Gnomad NFE exome AF: 0.527

Gnomad OTH exome AF: 0.494

GnomAD4 exome AF: 0.524 AC: 765668 AN: 1461874 Hom.: 204573 Cov.: 85 AF XY: 0.521 AC XY: 379248 AN XY: 727236

Gnomad4 AFR exome AF: 0.872

Gnomad4 AMR exome AF: 0.320

Gnomad4 ASJ exome AF: 0.525

Gnomad4 EAS exome AF: 0.448

Gnomad4 SAS exome AF: 0.448

Gnomad4 FIN exome AF: 0.440

Gnomad4 NFE exome AF: 0.533

Gnomad4 OTH exome AF: 0.535

GnomAD4 genome AF: 0.595 AC: 90387 AN: 151986 Hom.: 29065 Cov.: 32 AF XY: 0.583 AC XY: 43339 AN XY: 74294

Gnomad4 AFR AF: 0.859

Gnomad4 AMR AF: 0.423

Gnomad4 ASJ AF: 0.524

Gnomad4 EAS AF: 0.462

Gnomad4 SAS AF: 0.444

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.526

Gnomad4 OTH AF: 0.544

Alfa AF: 0.536 Hom.: 57369

Bravo AF: 0.608

TwinsUK AF: 0.542 AC: 2011

ALSPAC AF: 0.538 AC: 2074

ESP6500AA AF: 0.847 AC: 3726

ESP6500EA AF: 0.525 AC: 4515

ExAC AF: 0.510 AC: 61877

Asia WGS AF: 0.474 AC: 1649 AN: 3478

EpiCase AF: 0.526

EpiControl AF: 0.520

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.10
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.087	T;T
MetaRNN	Benign	0.0000056	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.12	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.70	N;N
REVEL	Benign	0.014
Sift	Benign	0.66	T;T
Sift4G	Benign	0.53	T;.
Polyphen		0.0	B;.
Vest4		0.020
MPC		0.29
ClinPred		0.0019	T
GERP RS		-5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.098
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs25653; hg19: chr15-90349558; COSMIC: COSV55590480; COSMIC: COSV55590480;