4-110476566-C-T

Variant names:

• chr4-110476566-C-T
• rs199759636
• NM_001977.4:c.152C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001977.4(ENPEP):​c.152C>T​(p.Pro51Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,613,362 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (3 hom.)
• Consequence: ENPEP NM_001977.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0690
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007191479).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001977.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPEP	NM_001977.4	MANE Select	c.152C>T	p.Pro51Leu	missense	Exon 1 of 20	NP_001968.3
	ENPEP	NM_001379611.1		c.152C>T	p.Pro51Leu	missense	Exon 1 of 20	NP_001366540.1
	ENPEP	NM_001379612.1		c.152C>T	p.Pro51Leu	missense	Exon 1 of 19	NP_001366541.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPEP	ENST00000265162.10	TSL:1 MANE Select	c.152C>T	p.Pro51Leu	missense	Exon 1 of 20	ENSP00000265162.5	Q07075
	ENPEP	ENST00000876172.1		c.152C>T	p.Pro51Leu	missense	Exon 1 of 20	ENSP00000546231.1
	ENPEP	ENST00000876171.1		c.152C>T	p.Pro51Leu	missense	Exon 1 of 18	ENSP00000546230.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000395 AC: 99 AN: 250782 AF XY: 0.000413

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000229 AC: 335 AN: 1461068 Hom.: 3 Cov.: 30 AF XY: 0.000275 AC XY: 200 AN XY: 726712

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00171 AC: 147 AN: 86186

European-Finnish (FIN) AF: 0.000450 AC: 24 AN: 53342

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.000107 AC: 119 AN: 1111474

Other (OTH) AF: 0.000646 AC: 39 AN: 60372

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74478

African (AFR) AF: 0.0000241 AC: 1 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000103 Hom.: 1

Bravo AF: 0.0000453

ExAC AF: 0.000511 AC: 62

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.2
DANN	Benign	0.60
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.069
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.040
Sift	Benign	0.32	T
Sift4G	Benign	0.47	T
Polyphen		0.0070	B
Vest4		0.14
MVP		0.18
MPC		0.11
ClinPred		0.011	T
GERP RS		-1.2
PromoterAI		-0.044	Neutral
Varity_R		0.027
gMVP		0.44
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs199759636; hg19: chr4-111397722; COSMIC: COSV54448836;