NM_001040458.3:c.2174G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001040458.3(ERAP1):c.2174G>A(p.Arg725Gln) variant causes a missense change. The variant allele was found at a frequency of 0.189 in 1,613,990 control chromosomes in the GnomAD database, including 31,360 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.16 ( 2116 hom., cov: 33)

Exomes 𝑓: 0.19 ( 29244 hom. )

Consequence

ERAP1
NM_001040458.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.74

Publications

148 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=0.0016841888).

BP6

Variant 5-96783162-C-T is Benign according to our data. Variant chr5-96783162-C-T is described in ClinVar as Benign. ClinVar VariationId is 2688505.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040458.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERAP1	NM_001040458.3	MANE Select	c.2174G>A	p.Arg725Gln	missense	Exon 15 of 19	NP_001035548.1
ERAP1	NM_001349244.2		c.2174G>A	p.Arg725Gln	missense	Exon 15 of 20	NP_001336173.1
ERAP1	NM_016442.5		c.2174G>A	p.Arg725Gln	missense	Exon 15 of 20	NP_057526.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERAP1	ENST00000443439.7	TSL:1 MANE Select	c.2174G>A	p.Arg725Gln	missense	Exon 15 of 19	ENSP00000406304.2
ERAP1	ENST00000296754.7	TSL:1	c.2174G>A	p.Arg725Gln	missense	Exon 15 of 20	ENSP00000296754.3
ERAP1	ENST00000514604.5	TSL:5	n.598G>A		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes

AF:

0.155

AC:

23586

AN:

152120

Hom.:

2114

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0843

Gnomad AMI

AF:

0.117

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.0469

Gnomad SAS

AF:

0.0872

Gnomad FIN

AF:

0.202

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.211

Gnomad OTH

AF:

0.133

GnomAD2 exomes

AF:

0.150

AC:

37678

AN:

251358

AF XY:

0.151

show subpopulations

Gnomad AFR exome

AF:

0.0852

Gnomad AMR exome

AF:

0.0870

Gnomad ASJ exome

AF:

0.124

Gnomad EAS exome

AF:

0.0487

Gnomad FIN exome

AF:

0.198

Gnomad NFE exome

AF:

0.203

Gnomad OTH exome

AF:

0.157

GnomAD4 exome

AF:

0.192

AC:

280983

AN:

1461752

Hom.:

29244

Cov.:

AF XY:

0.190

AC XY:

137974

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.0824

AC:

2758

AN:

33480

American (AMR)

AF:

0.0907

AC:

4058

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

3323

AN:

26132

East Asian (EAS)

AF:

0.0449

AC:

1781

AN:

39678

South Asian (SAS)

AF:

0.0940

AC:

8110

AN:

86256

European-Finnish (FIN)

AF:

0.191

AC:

10190

AN:

53414

Middle Eastern (MID)

AF:

0.0976

AC:

563

AN:

5768

European-Non Finnish (NFE)

AF:

0.216

AC:

239735

AN:

1111912

Other (OTH)

AF:

0.173

AC:

10465

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

11872

23744

35616

47488

59360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8120

16240

24360

32480

40600

<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:

0.155

AC:

23598

AN:

152238

Hom.:

2116

Cov.:

AF XY:

0.153

AC XY:

11386

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0841

AC:

3494

AN:

41548

American (AMR)

AF:

0.136

AC:

2077

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

434

AN:

3470

East Asian (EAS)

AF:

0.0472

AC:

245

AN:

5186

South Asian (SAS)

AF:

0.0881

AC:

426

AN:

4834

European-Finnish (FIN)

AF:

0.202

AC:

2138

AN:

10586

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.211

AC:

14365

AN:

67998

Other (OTH)

AF:

0.134

AC:

284

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1008

2016

3024

4032

5040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

262

524

786

1048

1310

<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:

0.181

Hom.:

9254

Bravo

AF:

0.148

TwinsUK

AF:

0.216

AC:

801

ALSPAC

AF:

0.218

AC:

841

ESP6500AA

AF:

0.0958

AC:

422

ESP6500EA

AF:

0.205

AC:

1762

ExAC

AF:

0.150

AC:

18224

Asia WGS

AF:

0.0890

AC:

309

AN:

3478

EpiCase

AF:

0.198

EpiControl

AF:

0.199

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 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.076

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.1

PhyloP100

4.7

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.3

REVEL

Benign

0.15

Sift

Benign

0.13

Sift4G

Benign

0.084

Polyphen

0.76

Vest4

0.15

MPC

0.13

ClinPred

0.011

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.62

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over