chr5-96803547-C-G

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.380G>C(p.Arg127Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.684 in 1,613,416 control chromosomes in the GnomAD database, including 381,926 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.63 ( 31291 hom., cov: 31)

Exomes 𝑓: 0.69 ( 350635 hom. )

Consequence

ERAP1
NM_001040458.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.537

Publications

133 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:

ENSG00000272109 (HGNC:):

ENSG00000272109 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=2.399225E-6).

BP6

Variant 5-96803547-C-G is Benign according to our data. Variant chr5-96803547-C-G is described in ClinVar as Benign. ClinVar VariationId is 2688544.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.715 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.380G>C	p.Arg127Pro	missense	Exon 2 of 19	NP_001035548.1
ERAP1	NM_001349244.2		c.380G>C	p.Arg127Pro	missense	Exon 2 of 20	NP_001336173.1
ERAP1	NM_016442.5		c.380G>C	p.Arg127Pro	missense	Exon 2 of 20	NP_057526.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERAP1	ENST00000443439.7	TSL:1 MANE Select	c.380G>C	p.Arg127Pro	missense	Exon 2 of 19	ENSP00000406304.2
ERAP1	ENST00000296754.7	TSL:1	c.380G>C	p.Arg127Pro	missense	Exon 2 of 20	ENSP00000296754.3
ERAP1	ENST00000507154.1	TSL:3	c.380G>C	p.Arg127Pro	missense	Exon 3 of 3	ENSP00000421697.1

Frequencies

GnomAD3 genomes

AF:

0.634

AC:

96341

AN:

151902

Hom.:

31278

Cov.:

show subpopulations

Gnomad AFR

AF:

0.525

Gnomad AMI

AF:

0.590

Gnomad AMR

AF:

0.585

Gnomad ASJ

AF:

0.577

Gnomad EAS

AF:

0.486

Gnomad SAS

AF:

0.546

Gnomad FIN

AF:

0.719

Gnomad MID

AF:

0.614

Gnomad NFE

AF:

0.720

Gnomad OTH

AF:

0.620

GnomAD2 exomes

AF:

0.637

AC:

160097

AN:

251238

AF XY:

0.640

show subpopulations

Gnomad AFR exome

AF:

0.526

Gnomad AMR exome

AF:

0.558

Gnomad ASJ exome

AF:

0.580

Gnomad EAS exome

AF:

0.455

Gnomad FIN exome

AF:

0.716

Gnomad NFE exome

AF:

0.719

Gnomad OTH exome

AF:

0.659

GnomAD4 exome

AF:

0.689

AC:

1006403

AN:

1461396

Hom.:

350635

Cov.:

AF XY:

0.686

AC XY:

498432

AN XY:

726916

show subpopulations

African (AFR)

AF:

0.514

AC:

17218

AN:

33470

American (AMR)

AF:

0.562

AC:

25132

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.585

AC:

15283

AN:

26114

East Asian (EAS)

AF:

0.487

AC:

19316

AN:

39684

South Asian (SAS)

AF:

0.541

AC:

46671

AN:

86252

European-Finnish (FIN)

AF:

0.714

AC:

38149

AN:

53418

Middle Eastern (MID)

AF:

0.608

AC:

3508

AN:

5766

European-Non Finnish (NFE)

AF:

0.721

AC:

801202

AN:

1111600

Other (OTH)

AF:

0.661

AC:

39924

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

19441

38882

58324

77765

97206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19758

39516

59274

79032

98790

<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:

0.634

AC:

96391

AN:

152020

Hom.:

31291

Cov.:

AF XY:

0.631

AC XY:

46906

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.525

AC:

21741

AN:

41416

American (AMR)

AF:

0.585

AC:

8945

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.577

AC:

2001

AN:

3466

East Asian (EAS)

AF:

0.485

AC:

2506

AN:

5166

South Asian (SAS)

AF:

0.546

AC:

2625

AN:

4812

European-Finnish (FIN)

AF:

0.719

AC:

7602

AN:

10578

Middle Eastern (MID)

AF:

0.626

AC:

184

AN:

294

European-Non Finnish (NFE)

AF:

0.720

AC:

48940

AN:

67986

Other (OTH)

AF:

0.621

AC:

1309

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1706

3412

5117

6823

8529

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

782

1564

2346

3128

3910

<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:

0.663

Hom.:

8915

Bravo

AF:

0.619

TwinsUK

AF:

0.711

AC:

2638

ALSPAC

AF:

0.713

AC:

2746

ESP6500AA

AF:

0.526

AC:

2319

ESP6500EA

AF:

0.709

AC:

6094

ExAC

AF:

0.638

AC:

77506

Asia WGS

AF:

0.568

AC:

1976

AN:

3478

EpiCase

AF:

0.712

EpiControl

AF:

0.704

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 84% of patients studied by a panel of primary immunodeficiencies. Number of patients: 74. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.8

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.0097

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0020

LIST_S2

Benign

0.070

MetaRNN

Benign

0.0000024

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.6

PhyloP100

0.54

PrimateAI

Benign

0.24

PROVEAN

Benign

1.2

REVEL

Benign

0.044

Sift

Benign

0.23

Sift4G

Benign

0.32

Polyphen

0.0

Vest4

0.082

MPC

0.11

ClinPred

0.0071

GERP RS

3.7

Varity_R

0.61

gMVP

0.59

Mutation Taster

=99/1

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

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