rs8192297

Positions:

• chr15-89801121-T-C

Variant summary

Our verdict is Benign. Variant got -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. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I603K) has been classified as Likely benign.

• 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

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=1.4510751E-4).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANPEP	NM_001150.3	c.1809A>G	p.Ile603Met	missense_variant	12/21	ENST00000300060.7	NP_001141.2
ANPEP	NM_001381923.1	c.1809A>G	p.Ile603Met	missense_variant	12/21		NP_001368852.1
ANPEP	NM_001381924.1	c.1809A>G	p.Ile603Met	missense_variant	11/20		NP_001368853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANPEP	ENST00000300060.7	c.1809A>G	p.Ile603Met	missense_variant	12/21	1	NM_001150.3	ENSP00000300060	P1

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

GnomAD3 exomes AF: 0.210 AC: 52709 AN: 251312 Hom.: 7607 AF XY: 0.198 AC XY: 26958 AN XY: 135830

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 SAS exome AF: 0.195

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

Gnomad4 AFR exome AF: 0.182

Gnomad4 AMR exome AF: 0.472

Gnomad4 ASJ exome AF: 0.261

Gnomad4 EAS exome AF: 0.283

Gnomad4 SAS exome AF: 0.193

Gnomad4 FIN exome AF: 0.160

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.171

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

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.361

Gnomad4 ASJ AF: 0.256

Gnomad4 EAS AF: 0.273

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.179

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.219

Alfa AF: 0.153 Hom.: 3695

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 v4.3

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
MutationTaster	Benign	1.0	P
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

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

Publications

LitVar

Other links and lift over

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