rs25651

Variant names:

• chr15-89792557-C-T
• rs25651
• NM_001150.3:c.2255G>A

Variant summary

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

The NM_001150.3(ANPEP):​c.2255G>A​(p.Ser752Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 1,612,620 control chromosomes in the GnomAD database, including 84,996 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 0.35 (10156 hom., cov: 32)
  • Exomes 𝑓: 0.32 (74840 hom.)
• Consequence: ANPEP NM_001150.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0940
• Publications: 43 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=3.1119915E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.492 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.2255G>A	p.Ser752Asn	missense	Exon 17 of 21	NP_001141.2	P15144
	ANPEP	NM_001381923.1		c.2255G>A	p.Ser752Asn	missense	Exon 17 of 21	NP_001368852.1	P15144
	ANPEP	NM_001381924.1		c.2255G>A	p.Ser752Asn	missense	Exon 16 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.2255G>A	p.Ser752Asn	missense	Exon 17 of 21	ENSP00000300060.6	P15144
	ANPEP	ENST00000559874.2	TSL:3	c.2255G>A	p.Ser752Asn	missense	Exon 17 of 21	ENSP00000452934.2	P15144
	ANPEP	ENST00000560137.2	TSL:3	c.2255G>A	p.Ser752Asn	missense	Exon 17 of 21	ENSP00000453413.2	P15144

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53420 AN: 151886 Hom.: 10146 Cov.: 32

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.325

GnomAD2 exomes AF: 0.301 AC: 75567 AN: 251026 AF XY: 0.302

Gnomad AFR exome AF: 0.496

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.240

Gnomad FIN exome AF: 0.205

Gnomad NFE exome AF: 0.317

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.316 AC: 461669 AN: 1460616 Hom.: 74840 Cov.: 36 AF XY: 0.316 AC XY: 229727 AN XY: 726728

African (AFR) AF: 0.502 AC: 16787 AN: 33450

American (AMR) AF: 0.242 AC: 10806 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 6625 AN: 26120

East Asian (EAS) AF: 0.227 AC: 9021 AN: 39690

South Asian (SAS) AF: 0.329 AC: 28394 AN: 86238

European-Finnish (FIN) AF: 0.216 AC: 11527 AN: 53394

Middle Eastern (MID) AF: 0.283 AC: 1635 AN: 5768

European-Non Finnish (NFE) AF: 0.322 AC: 357983 AN: 1110908

Other (OTH) AF: 0.313 AC: 18891 AN: 60348

GnomAD4 genome AF: 0.352 AC: 53481 AN: 152004 Hom.: 10156 Cov.: 32 AF XY: 0.342 AC XY: 25416 AN XY: 74324

African (AFR) AF: 0.497 AC: 20608 AN: 41444

American (AMR) AF: 0.274 AC: 4192 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 881 AN: 3468

East Asian (EAS) AF: 0.235 AC: 1209 AN: 5154

South Asian (SAS) AF: 0.340 AC: 1641 AN: 4822

European-Finnish (FIN) AF: 0.194 AC: 2060 AN: 10598

Middle Eastern (MID) AF: 0.267 AC: 78 AN: 292

European-Non Finnish (NFE) AF: 0.318 AC: 21579 AN: 67930

Other (OTH) AF: 0.325 AC: 688 AN: 2114

Alfa AF: 0.326 Hom.: 37432

Bravo AF: 0.363

TwinsUK AF: 0.328 AC: 1218

ALSPAC AF: 0.329 AC: 1267

ESP6500AA AF: 0.487 AC: 2142

ESP6500EA AF: 0.318 AC: 2737

ExAC AF: 0.309 AC: 37509

Asia WGS AF: 0.297 AC: 1037 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.010
DANN	Benign	0.13
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.000031	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.99	N
PhyloP100		0.094
PrimateAI	Benign	0.29	T
PROVEAN	Benign	3.0	N
REVEL	Benign	0.085
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.047
MPC		0.24
ClinPred		0.000023	T
GERP RS		-4.4
Varity_R		0.055
gMVP		0.35
Mutation Taster		=98/2	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: rs25651; hg19: chr15-90335788; COSMIC: COSV55591836; COSMIC: COSV55591836;