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

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

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

Publications

88 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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

GnomAD2 exomes

AF:

0.224

AC:

56187

AN:

250962

AF XY:

0.228

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 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

African (AFR)

AF:

0.204

AC:

6813

AN:

33462

American (AMR)

AF:

0.152

AC:

6800

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.195

AC:

5092

AN:

26130

East Asian (EAS)

AF:

0.260

AC:

10295

AN:

39672

South Asian (SAS)

AF:

0.231

AC:

19888

AN:

86248

European-Finnish (FIN)

AF:

0.231

AC:

12308

AN:

53250

Middle Eastern (MID)

AF:

0.199

AC:

1145

AN:

5768

European-Non Finnish (NFE)

AF:

0.236

AC:

262677

AN:

1111682

Other (OTH)

AF:

0.229

AC:

13832

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

14013

28026

42040

56053

70066

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8818

17636

26454

35272

44090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.223

AC:

33837

AN:

151990

Hom.:

3818

Cov.:

AF XY:

0.222

AC XY:

16468

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.207

AC:

8582

AN:

41448

American (AMR)

AF:

0.183

AC:

2798

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.194

AC:

675

AN:

3472

East Asian (EAS)

AF:

0.270

AC:

1387

AN:

5140

South Asian (SAS)

AF:

0.234

AC:

1124

AN:

4812

European-Finnish (FIN)

AF:

0.216

AC:

2283

AN:

10574

Middle Eastern (MID)

AF:

0.202

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.239

AC:

16263

AN:

67982

Other (OTH)

AF:

0.227

AC:

480

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1312

2624

3935

5247

6559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

366

732

1098

1464

1830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.234

Hom.:

20649

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

(source)

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

PhyloP100

-0.64

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

Mutation Taster

=87/13

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over