Genetic Variant NM_001040458.3:c.1583A>G (chr5-96788627-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.1583A>G(p.Lys528Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.644 in 1,613,788 control chromosomes in the GnomAD database, including 336,155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.62 ( 29841 hom., cov: 32)

Exomes 𝑓: 0.65 ( 306314 hom. )

Consequence

ERAP1
NM_001040458.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.43

Publications

320 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=1.2251857E-4).

BP6

Variant 5-96788627-T-C is Benign according to our data. Variant chr5-96788627-T-C is described in ClinVar as Benign. ClinVar VariationId is 2688359.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERAP1	NM_001040458.3 link	c.1583A>G	p.Lys528Arg	missense_variant	Exon 11 of 19	ENST00000443439.7	NP_001035548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ERAP1	ENST00000443439.7 link	c.1583A>G	p.Lys528Arg	missense_variant	Exon 11 of 19	1	NM_001040458.3	ENSP00000406304.2
ERAP1	ENST00000296754.7 link	c.1583A>G	p.Lys528Arg	missense_variant	Exon 11 of 20	1		ENSP00000296754.3
ERAP1	ENST00000507859.1 link	n.246A>G		non_coding_transcript_exon_variant	Exon 3 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.624

AC:

94853

AN:

151930

Hom.:

29810

Cov.:

show subpopulations

Gnomad AFR

AF:

0.604

Gnomad AMI

AF:

0.448

Gnomad AMR

AF:

0.595

Gnomad ASJ

AF:

0.561

Gnomad EAS

AF:

0.514

Gnomad SAS

AF:

0.588

Gnomad FIN

AF:

0.646

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.658

Gnomad OTH

AF:

0.567

GnomAD2 exomes

AF:

0.620

AC:

155788

AN:

251240

AF XY:

0.621

show subpopulations

Gnomad AFR exome

AF:

0.608

Gnomad AMR exome

AF:

0.611

Gnomad ASJ exome

AF:

0.557

Gnomad EAS exome

AF:

0.480

Gnomad FIN exome

AF:

0.653

Gnomad NFE exome

AF:

0.654

Gnomad OTH exome

AF:

0.615

GnomAD4 exome

AF:

0.646

AC:

943908

AN:

1461740

Hom.:

306314

Cov.:

AF XY:

0.644

AC XY:

468530

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.598

AC:

20027

AN:

33478

American (AMR)

AF:

0.609

AC:

27213

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.559

AC:

14597

AN:

26136

East Asian (EAS)

AF:

0.515

AC:

20440

AN:

39686

South Asian (SAS)

AF:

0.586

AC:

50567

AN:

86256

European-Finnish (FIN)

AF:

0.653

AC:

34847

AN:

53400

Middle Eastern (MID)

AF:

0.594

AC:

3427

AN:

5768

European-Non Finnish (NFE)

AF:

0.661

AC:

735148

AN:

1111920

Other (OTH)

AF:

0.623

AC:

37642

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

19734

39467

59201

78934

98668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19092

38184

57276

76368

95460

<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:

0.624

AC:

94930

AN:

152048

Hom.:

29841

Cov.:

AF XY:

0.621

AC XY:

46193

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.604

AC:

25056

AN:

41458

American (AMR)

AF:

0.596

AC:

9107

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.561

AC:

1948

AN:

3470

East Asian (EAS)

AF:

0.513

AC:

2652

AN:

5166

South Asian (SAS)

AF:

0.587

AC:

2828

AN:

4816

European-Finnish (FIN)

AF:

0.646

AC:

6822

AN:

10554

Middle Eastern (MID)

AF:

0.510

AC:

150

AN:

294

European-Non Finnish (NFE)

AF:

0.658

AC:

44755

AN:

67982

Other (OTH)

AF:

0.569

AC:

1203

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1832

3664

5497

7329

9161

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:

0.639

Hom.:

144447

Bravo

AF:

0.617

TwinsUK

AF:

0.660

AC:

2447

ALSPAC

AF:

0.660

AC:

2544

ESP6500AA

AF:

0.597

AC:

2629

ESP6500EA

AF:

0.643

AC:

5533

ExAC

AF:

0.620

AC:

75310

Asia WGS

AF:

0.593

AC:

2063

AN:

3478

EpiCase

AF:

0.652

EpiControl

AF:

0.641

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 78% of patients studied by a panel of primary immunodeficiencies. Number of patients: 69. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

.;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.00012

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.7

H;H

PhyloP100

7.4

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.18

Sift

Benign

0.073

T;T

Sift4G

Benign

0.10

T;T

Polyphen

1.0

D;D

Vest4

0.14

MPC

0.19

ClinPred

0.10

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.61

Mutation Taster

=92/8

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