chr4-110476522-C-T

Variant names:

• chr4-110476522-C-T
• rs76248418
• NM_001977.4:c.108C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001977.4(ENPEP):​c.108C>T​(p.Ala36Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,603,474 control chromosomes in the GnomAD database, including 371 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (190 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (181 hom.)
• Consequence: ENPEP NM_001977.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.94
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 4-110476522-C-T is Benign according to our data. Variant chr4-110476522-C-T is described in ClinVar as Benign. ClinVar VariationId is 780491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.94 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0891 is higher than 0.05.

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.108C>T	p.Ala36Ala	synonymous	Exon 1 of 20	NP_001968.3
	ENPEP	NM_001379611.1		c.108C>T	p.Ala36Ala	synonymous	Exon 1 of 20	NP_001366540.1
	ENPEP	NM_001379612.1		c.108C>T	p.Ala36Ala	synonymous	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.108C>T	p.Ala36Ala	synonymous	Exon 1 of 20	ENSP00000265162.5	Q07075
	ENPEP	ENST00000876172.1		c.108C>T	p.Ala36Ala	synonymous	Exon 1 of 20	ENSP00000546231.1
	ENPEP	ENST00000876171.1		c.108C>T	p.Ala36Ala	synonymous	Exon 1 of 18	ENSP00000546230.1

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4014 AN: 152100 Hom.: 189 Cov.: 32

Gnomad AFR AF: 0.0915

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00695 AC: 1706 AN: 245502 AF XY: 0.00528

Gnomad AFR exome AF: 0.0913

Gnomad AMR exome AF: 0.00476

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000306

Gnomad OTH exome AF: 0.00402

GnomAD4 exome AF: 0.00286 AC: 4146 AN: 1451256 Hom.: 181 Cov.: 30 AF XY: 0.00251 AC XY: 1811 AN XY: 720208

African (AFR) AF: 0.0973 AC: 3244 AN: 33324

American (AMR) AF: 0.00519 AC: 230 AN: 44308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25356

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39506

South Asian (SAS) AF: 0.000153 AC: 13 AN: 84864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53010

Middle Eastern (MID) AF: 0.00718 AC: 41 AN: 5712

European-Non Finnish (NFE) AF: 0.000232 AC: 256 AN: 1105256

Other (OTH) AF: 0.00602 AC: 361 AN: 59920

GnomAD4 genome AF: 0.0264 AC: 4024 AN: 152218 Hom.: 190 Cov.: 32 AF XY: 0.0263 AC XY: 1961 AN XY: 74430

African (AFR) AF: 0.0916 AC: 3801 AN: 41512

American (AMR) AF: 0.0105 AC: 161 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68020

Other (OTH) AF: 0.0156 AC: 33 AN: 2110

Alfa AF: 0.0124 Hom.: 38

Bravo AF: 0.0303

Asia WGS AF: 0.00520 AC: 19 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.61
DANN	Benign	0.78
PhyloP100		-5.9
PromoterAI		-0.023	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs76248418; hg19: chr4-111397678;