Genetic Variant ERAP1:p.Ala637Ala (chr5-96785820-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BA1

The NM_001040458.3(ERAP1):c.1911G>A(p.Ala637Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,613,624 control chromosomes in the GnomAD database, including 259,719 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.56 ( 24113 hom., cov: 31)

Exomes 𝑓: 0.57 ( 235606 hom. )

Consequence

ERAP1
NM_001040458.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.381

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:

ENSG00000248734 (HGNC:):

ENSG00000248734 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 5-96785820-C-T is Benign according to our data. Variant chr5-96785820-C-T is described in ClinVar as [Benign]. Clinvar id is 2688369.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.381 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERAP1	NM_001040458.3 link	c.1911G>A	p.Ala637Ala	synonymous_variant	Exon 13 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.1911G>A	p.Ala637Ala	synonymous_variant	Exon 13 of 19	1	NM_001040458.3	ENSP00000406304.2		Q9NZ08-1

Frequencies

GnomAD3 genomes

AF:

0.562

AC:

85363

AN:

151846

Hom.:

24076

Cov.:

show subpopulations

Gnomad AFR

AF:

0.579

Gnomad AMI

AF:

0.359

Gnomad AMR

AF:

0.549

Gnomad ASJ

AF:

0.450

Gnomad EAS

AF:

0.513

Gnomad SAS

AF:

0.538

Gnomad FIN

AF:

0.573

Gnomad MID

AF:

0.378

Gnomad NFE

AF:

0.570

Gnomad OTH

AF:

0.498

GnomAD3 exomes

AF:

0.554

AC:

139079

AN:

251214

Hom.:

38758

AF XY:

0.551

AC XY:

74786

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.587

Gnomad AMR exome

AF:

0.577

Gnomad ASJ exome

AF:

0.442

Gnomad EAS exome

AF:

0.479

Gnomad SAS exome

AF:

0.538

Gnomad FIN exome

AF:

0.579

Gnomad NFE exome

AF:

0.564

Gnomad OTH exome

AF:

0.540

GnomAD4 exome

AF:

0.566

AC:

827802

AN:

1461660

Hom.:

235606

Cov.:

AF XY:

0.565

AC XY:

410624

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.574

Gnomad4 AMR exome

AF:

0.574

Gnomad4 ASJ exome

AF:

0.445

Gnomad4 EAS exome

AF:

0.514

Gnomad4 SAS exome

AF:

0.527

Gnomad4 FIN exome

AF:

0.579

Gnomad4 NFE exome

AF:

0.575

Gnomad4 OTH exome

AF:

0.548

GnomAD4 genome

AF:

0.562

AC:

85449

AN:

151964

Hom.:

24113

Cov.:

AF XY:

0.562

AC XY:

41721

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.579

Gnomad4 AMR

AF:

0.550

Gnomad4 ASJ

AF:

0.450

Gnomad4 EAS

AF:

0.512

Gnomad4 SAS

AF:

0.536

Gnomad4 FIN

AF:

0.573

Gnomad4 NFE

AF:

0.570

Gnomad4 OTH

AF:

0.500

Alfa

AF:

0.549

Hom.:

18455

Bravo

AF:

0.558

Asia WGS

AF:

0.565

AC:

1967

AN:

3478

EpiCase

AF:

0.558

EpiControl

AF:

0.544

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 74% of patients studied by a panel of primary immunodeficiencies. Number of patients: 65. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.81

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: 3

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