rs8192297

Variant names:

• chr15-89801121-T-C
• rs8192297
• NM_001150.3:c.1809A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001150.3(ANPEP):​c.1809A>G​(p.Ile603Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,613,368 control chromosomes in the GnomAD database, including 22,886 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2935 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19951 hom.)
• Consequence: ANPEP NM_001150.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.40
• Publications: 34 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4510751E-4).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001150.3. 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
	ANPEP	NM_001150.3	MANE Select	c.1809A>G	p.Ile603Met	missense	Exon 12 of 21	NP_001141.2	P15144
	ANPEP	NM_001381923.1		c.1809A>G	p.Ile603Met	missense	Exon 12 of 21	NP_001368852.1	P15144
	ANPEP	NM_001381924.1		c.1809A>G	p.Ile603Met	missense	Exon 11 of 20	NP_001368853.1	P15144

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANPEP	ENST00000300060.7	TSL:1 MANE Select	c.1809A>G	p.Ile603Met	missense	Exon 12 of 21	ENSP00000300060.6	P15144
	ANPEP	ENST00000559874.2	TSL:3	c.1809A>G	p.Ile603Met	missense	Exon 12 of 21	ENSP00000452934.2	P15144
	ANPEP	ENST00000560137.2	TSL:3	c.1809A>G	p.Ile603Met	missense	Exon 12 of 21	ENSP00000453413.2	P15144

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27141 AN: 152020 Hom.: 2909 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.213

GnomAD2 exomes AF: 0.210 AC: 52709 AN: 251312 AF XY: 0.198

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.493

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.274

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.147 AC: 215153 AN: 1461230 Hom.: 19951 Cov.: 32 AF XY: 0.148 AC XY: 107224 AN XY: 726904

African (AFR) AF: 0.182 AC: 6089 AN: 33464

American (AMR) AF: 0.472 AC: 21097 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 6829 AN: 26132

East Asian (EAS) AF: 0.283 AC: 11219 AN: 39686

South Asian (SAS) AF: 0.193 AC: 16631 AN: 86238

European-Finnish (FIN) AF: 0.160 AC: 8530 AN: 53338

Middle Eastern (MID) AF: 0.218 AC: 1254 AN: 5758

European-Non Finnish (NFE) AF: 0.120 AC: 133186 AN: 1111546

Other (OTH) AF: 0.171 AC: 10318 AN: 60358

GnomAD4 genome AF: 0.179 AC: 27206 AN: 152138 Hom.: 2935 Cov.: 32 AF XY: 0.188 AC XY: 13998 AN XY: 74368

African (AFR) AF: 0.175 AC: 7249 AN: 41510

American (AMR) AF: 0.361 AC: 5522 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 888 AN: 3472

East Asian (EAS) AF: 0.273 AC: 1405 AN: 5154

South Asian (SAS) AF: 0.197 AC: 948 AN: 4824

European-Finnish (FIN) AF: 0.179 AC: 1891 AN: 10588

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8593 AN: 67980

Other (OTH) AF: 0.219 AC: 464 AN: 2116

Alfa AF: 0.151 Hom.: 7720

Bravo AF: 0.195

TwinsUK AF: 0.116 AC: 431

ALSPAC AF: 0.128 AC: 492

ESP6500AA AF: 0.168 AC: 739

ESP6500EA AF: 0.129 AC: 1107

ExAC AF: 0.195 AC: 23622

Asia WGS AF: 0.251 AC: 874 AN: 3478

EpiCase AF: 0.137

EpiControl AF: 0.140

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.0050
DANN	Benign	0.37
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.091	T
MetaRNN	Benign	0.00015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.53	N
PhyloP100		-2.4
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.041
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.021
MPC		0.26
ClinPred		0.0037	T
GERP RS		-5.0
Varity_R		0.38
gMVP		0.37
Mutation Taster		=100/0	polymorphism (auto)

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: rs8192297; hg19: chr15-90344352; COSMIC: COSV55589989; COSMIC: COSV55589989;