rs370461277

Variant names:

• chr15-89785462-C-A
• rs370461277
• NM_001150.3:c.2791G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-89785462-C-A
• chr15-89785462-C-G
• chr15-89785462-C-T

Variant summary

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

The NM_001150.3(ANPEP):​c.2791G>T​(p.Gly931Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G931S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANPEP NM_001150.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.54

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, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANPEP	NM_001150.3	c.2791G>T	p.Gly931Cys	missense_variant	Exon 21 of 21	ENST00000300060.7	NP_001141.2
ANPEP	NM_001381923.1	c.2791G>T	p.Gly931Cys	missense_variant	Exon 21 of 21		NP_001368852.1
ANPEP	NM_001381924.1	c.2791G>T	p.Gly931Cys	missense_variant	Exon 20 of 20		NP_001368853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANPEP	ENST00000300060.7	c.2791G>T	p.Gly931Cys	missense_variant	Exon 21 of 21	1	NM_001150.3	ENSP00000300060.6
ANPEP	ENST00000559874.2	c.2791G>T	p.Gly931Cys	missense_variant	Exon 21 of 21	3		ENSP00000452934.2
ANPEP	ENST00000560137.2	c.2791G>T	p.Gly931Cys	missense_variant	Exon 21 of 21	3		ENSP00000453413.2
ANPEP	ENST00000679248.1	c.2791G>T	p.Gly931Cys	missense_variant	Exon 22 of 22			ENSP00000502886.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249088 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461760 Hom.: 0 Cov.: 56 AF XY: 0.00 AC XY: 0 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.5	H
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.40		Loss of disorder (P = 0.0126);
MVP		0.71
MPC		0.94
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.86

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: rs370461277; hg19: chr15-90328693;