Genetic Variant ERAP1:p.Ile276Met (chr5-96795133-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001040458.3(ERAP1):c.828A>G(p.Ile276Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,613,306 control chromosomes in the GnomAD database, including 43,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.22 ( 3818 hom., cov: 32)

Exomes 𝑓: 0.23 ( 39655 hom. )

Consequence

ERAP1
NM_001040458.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.636

Variant links:

Genes affected

ERAP1 (HGNC:18173): (endoplasmic reticulum aminopeptidase 1) The protein encoded by this gene is an aminopeptidase involved in trimming HLA class I-binding precursors so that they can be presented on MHC class I molecules. The encoded protein acts as a monomer or as a heterodimer with ERAP2. This protein may also be involved in blood pressure regulation by inactivation of angiotensin II. Three transcript variants encoding two different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

ERAP1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016419888).

BP6

Variant 5-96795133-T-C is Benign according to our data. Variant chr5-96795133-T-C is described in ClinVar as [Benign]. Clinvar id is 2688460.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERAP1	NM_001040458.3 link	c.828A>G	p.Ile276Met	missense_variant	Exon 5 of 19	ENST00000443439.7	NP_001035548.1	Q9NZ08-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERAP1	ENST00000443439.7 link	c.828A>G	p.Ile276Met	missense_variant	Exon 5 of 19	1	NM_001040458.3	ENSP00000406304.2		Q9NZ08-1
ERAP1	ENST00000296754.7 link	c.828A>G	p.Ile276Met	missense_variant	Exon 5 of 20	1		ENSP00000296754.3		Q9NZ08-2

Frequencies

GnomAD3 genomes

AF:

0.223

AC:

33818

AN:

151870

Hom.:

3817

Cov.:

show subpopulations

Gnomad AFR

AF:

0.207

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.183

Gnomad ASJ

AF:

0.194

Gnomad EAS

AF:

0.271

Gnomad SAS

AF:

0.235

Gnomad FIN

AF:

0.216

Gnomad MID

AF:

0.207

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.225

GnomAD3 exomes

AF:

0.224

AC:

56187

AN:

250962

Hom.:

6483

AF XY:

0.228

AC XY:

30886

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.209

Gnomad AMR exome

AF:

0.146

Gnomad ASJ exome

AF:

0.191

Gnomad EAS exome

AF:

0.257

Gnomad SAS exome

AF:

0.239

Gnomad FIN exome

AF:

0.225

Gnomad NFE exome

AF:

0.242

Gnomad OTH exome

AF:

0.232

GnomAD4 exome

AF:

0.232

AC:

338850

AN:

1461316

Hom.:

39655

Cov.:

AF XY:

0.233

AC XY:

169062

AN XY:

726954

show subpopulations

Gnomad4 AFR exome

AF:

0.204

Gnomad4 AMR exome

AF:

0.152

Gnomad4 ASJ exome

AF:

0.195

Gnomad4 EAS exome

AF:

0.260

Gnomad4 SAS exome

AF:

0.231

Gnomad4 FIN exome

AF:

0.231

Gnomad4 NFE exome

AF:

0.236

Gnomad4 OTH exome

AF:

0.229

GnomAD4 genome

AF:

0.223

AC:

33837

AN:

151990

Hom.:

3818

Cov.:

AF XY:

0.222

AC XY:

16468

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.207

Gnomad4 AMR

AF:

0.183

Gnomad4 ASJ

AF:

0.194

Gnomad4 EAS

AF:

0.270

Gnomad4 SAS

AF:

0.234

Gnomad4 FIN

AF:

0.216

Gnomad4 NFE

AF:

0.239

Gnomad4 OTH

AF:

0.227

Alfa

AF:

0.234

Hom.:

10748

Bravo

AF:

0.215

TwinsUK

AF:

0.224

AC:

832

ALSPAC

AF:

0.233

AC:

898

ESP6500AA

AF:

0.202

AC:

889

ESP6500EA

AF:

0.228

AC:

1965

ExAC

AF:

0.227

AC:

27533

Asia WGS

AF:

0.270

AC:

940

AN:

3478

EpiCase

AF:

0.242

EpiControl

AF:

0.231

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 27. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

.;T

Eigen

Benign

-0.034

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.18

Sift

Benign

0.063

T;T

Sift4G

Benign

0.076

T;T

Polyphen

0.73

P;P

Vest4

0.18

MPC

0.25

ClinPred

0.045

GERP RS

-0.18

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.66

gMVP

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over