4-110476823-C-T

Variant names:

• chr4-110476823-C-T
• rs1341121359
• NM_001977.4:c.409C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001977.4(ENPEP):​c.409C>T​(p.Arg137Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ENPEP NM_001977.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.756

Genes affected

ENPEP (HGNC:3355): (glutamyl aminopeptidase) The ENPEP gene encodes glutamyl aminopeptidase, a type II integral membrane protein with an extracellular zinc-binding domain. This protein can upregulate blood pressure by cleaving the N-terminal aspartate from angiotensin II, and can regulate blood vessel formation and enhance tumorigenesis in some tissues. Along with ANPEP and DPP4, ENPEP was found to be a candidate co-receptor for the coronavirus SARS-CoV-2, which causes COVID-19. [provided by RefSeq, Apr 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPEP	NM_001977.4	c.409C>T	p.Arg137Trp	missense_variant	Exon 1 of 20	ENST00000265162.10	NP_001968.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPEP	ENST00000265162.10	c.409C>T	p.Arg137Trp	missense_variant	Exon 1 of 20	1	NM_001977.4	ENSP00000265162.5
ENPEP	ENST00000510961.1	n.73-11718C>T		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250920 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135748

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461852 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.409C>T (p.R137W) alteration is located in exon 1 (coding exon 1) of the ENPEP gene. This alteration results from a C to T substitution at nucleotide position 409, causing the arginine (R) at amino acid position 137 to be replaced by a tryptophan (W). 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	0.28
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.7	H
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.34
Sift	Benign	0.066	T
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.67		Gain of glycosylation at T142 (P = 0.0275);
MVP		0.43
MPC		0.55
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.75
gMVP		0.87

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: rs1341121359; hg19: chr4-111397979; COSMIC: COSV54452042;