chr5-96788627-T-C

Position:

• chr5-96788627-T-C

Variant summary

Our verdict is Benign. Variant got -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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
ERAP1	NM_001040458.3	c.1583A>G	p.Lys528Arg	missense_variant	11/19	ENST00000443439.7	NP_001035548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERAP1	ENST00000443439.7	c.1583A>G	p.Lys528Arg	missense_variant	11/19	1	NM_001040458.3	ENSP00000406304.2
ERAP1	ENST00000296754.7	c.1583A>G	p.Lys528Arg	missense_variant	11/20	1		ENSP00000296754.3
ERAP1	ENST00000507859.1	n.246A>G		non_coding_transcript_exon_variant	3/5	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

GnomAD3 exomes AF: 0.620 AC: 155788 AN: 251240 Hom.: 48690 AF XY: 0.621 AC XY: 84267 AN XY: 135782

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 SAS exome AF: 0.594

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

Gnomad4 AFR exome AF: 0.598

Gnomad4 AMR exome AF: 0.609

Gnomad4 ASJ exome AF: 0.559

Gnomad4 EAS exome AF: 0.515

Gnomad4 SAS exome AF: 0.586

Gnomad4 FIN exome AF: 0.653

Gnomad4 NFE exome AF: 0.661

Gnomad4 OTH exome AF: 0.623

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

Gnomad4 AFR AF: 0.604

Gnomad4 AMR AF: 0.596

Gnomad4 ASJ AF: 0.561

Gnomad4 EAS AF: 0.513

Gnomad4 SAS AF: 0.587

Gnomad4 FIN AF: 0.646

Gnomad4 NFE AF: 0.658

Gnomad4 OTH AF: 0.569

Alfa AF: 0.638 Hom.: 76596

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

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

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
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

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

LitVar

Other links and lift over

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