rs25651

chr15-89792557-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.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. 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 0.35 (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

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=3.1119915E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.492 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANPEP	NM_001150.3	c.2255G>A	p.Ser752Asn	missense_variant	17/21	ENST00000300060.7
ANPEP	NM_001381923.1	c.2255G>A	p.Ser752Asn	missense_variant	17/21
ANPEP	NM_001381924.1	c.2255G>A	p.Ser752Asn	missense_variant	16/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANPEP	ENST00000300060.7	c.2255G>A	p.Ser752Asn	missense_variant	17/21	1	NM_001150.3	P1

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

GnomAD3 exomes AF: 0.301 AC: 75567 AN: 251026 Hom.: 12120 AF XY: 0.302 AC XY: 41018 AN XY: 135706

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 SAS exome AF: 0.333

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

Gnomad4 AFR exome AF: 0.502

Gnomad4 AMR exome AF: 0.242

Gnomad4 ASJ exome AF: 0.254

Gnomad4 EAS exome AF: 0.227

Gnomad4 SAS exome AF: 0.329

Gnomad4 FIN exome AF: 0.216

Gnomad4 NFE exome AF: 0.322

Gnomad4 OTH exome AF: 0.313

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

Gnomad4 AFR AF: 0.497

Gnomad4 AMR AF: 0.274

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.235

Gnomad4 SAS AF: 0.340

Gnomad4 FIN AF: 0.194

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.325

Alfa AF: 0.319 Hom.: 18524

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 v4.3

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
MutationTaster	Benign	1.0	P
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

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: rs25651; hg19: chr15-90335788; COSMIC: COSV55591836; COSMIC: COSV55591836;