5-96788627-T-C

Variant names:

• chr5-96788627-T-C
• rs30187
• NM_001040458.3:c.1583A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.43
• Publications: 320 publications found

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]

ACMG classification

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	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	Appris	UniProt
ERAP1	ENST00000443439.7	c.1583A>G	p.Lys528Arg	missense_variant	Exon 11 of 19	1	NM_001040458.3	ENSP00000406304.2
ERAP1	ENST00000296754.7	c.1583A>G	p.Lys528Arg	missense_variant	Exon 11 of 20	1		ENSP00000296754.3
ERAP1	ENST00000507859.1	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.: 32

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

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.: 55 AF XY: 0.644 AC XY: 468530 AN XY: 727174

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

GnomAD4 genome AF: 0.624 AC: 94930 AN: 152048 Hom.: 29841 Cov.: 32 AF XY: 0.621 AC XY: 46193 AN XY: 74328

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

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

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	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.00012	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.7	H;H
PhyloP100		7.4
PrimateAI	Uncertain	0.61	T
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	T
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)

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

Other links and lift over

dbSNP: rs30187; hg19: chr5-96124330; COSMIC: COSV57085684; COSMIC: COSV57085684;