15-89799499-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001150.3(ANPEP):c.1880C>T(p.Thr627Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: ANPEP NM_001150.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANPEP	NM_001150.3	c.1880C>T	p.Thr627Met	missense_variant	13/21	ENST00000300060.7
ANPEP	NM_001381923.1	c.1880C>T	p.Thr627Met	missense_variant	13/21
ANPEP	NM_001381924.1	c.1880C>T	p.Thr627Met	missense_variant	12/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANPEP	ENST00000300060.7	c.1880C>T	p.Thr627Met	missense_variant	13/21	1	NM_001150.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000437 AC: 11 AN: 251462 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135908

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.0000371 AC XY: 27 AN XY: 727244

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74304

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2023

The c.1880C>T (p.T627M) alteration is located in exon 13 (coding exon 12) of the ANPEP gene. This alteration results from a C to T substitution at nucleotide position 1880, causing the threonine (T) at amino acid position 627 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	0.73	N
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.13
Sift	Benign	0.050	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.43
MVP		0.77
MPC		0.61
ClinPred		0.79	D
GERP RS		5.2
Varity_R		0.19
gMVP		0.74

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: rs149131671; hg19: chr15-90342730;