15-89790488-C-T

Variant names:

• chr15-89790488-C-T
• NM_001150.3:c.2723G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001150.3(ANPEP):​c.2723G>A​(p.Arg908Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANPEP NM_001150.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANPEP	NM_001150.3	c.2723G>A	p.Arg908Gln	missense_variant	Exon 20 of 21	ENST00000300060.7	NP_001141.2
ANPEP	NM_001381923.1	c.2723G>A	p.Arg908Gln	missense_variant	Exon 20 of 21		NP_001368852.1
ANPEP	NM_001381924.1	c.2723G>A	p.Arg908Gln	missense_variant	Exon 19 of 20		NP_001368853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANPEP	ENST00000300060.7	c.2723G>A	p.Arg908Gln	missense_variant	Exon 20 of 21	1	NM_001150.3	ENSP00000300060.6
ANPEP	ENST00000559874.2	c.2723G>A	p.Arg908Gln	missense_variant	Exon 20 of 21	3		ENSP00000452934.2
ANPEP	ENST00000560137.2	c.2723G>A	p.Arg908Gln	missense_variant	Exon 20 of 21	3		ENSP00000453413.2
ANPEP	ENST00000679248.1	c.2723G>A	p.Arg908Gln	missense_variant	Exon 21 of 22			ENSP00000502886.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2723G>A (p.R908Q) alteration is located in exon 20 (coding exon 19) of the ANPEP gene. This alteration results from a G to A substitution at nucleotide position 2723, causing the arginine (R) at amino acid position 908 to be replaced by a glutamine (Q). 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	0.27
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.22
Sift	Benign	0.11	T
Sift4G	Benign	0.27	T
Polyphen		0.81	P
Vest4		0.71
MutPred		0.40		Loss of phosphorylation at S910 (P = 0.0699);
MVP		0.60
MPC		0.53
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.77
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-90333719; COSMIC: COSV100263398; COSMIC: COSV100263398;