5-96803547-C-G

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.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. 14/20 in silico tools predict 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 0.63 (31291 hom., cov: 31)
  • Exomes 𝑓: 0.69 (350635 hom.)
• Consequence: ERAP1 NM_001040458.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.537

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERAP1	NM_001040458.3	c.380G>C	p.Arg127Pro	missense_variant	2/19	ENST00000443439.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERAP1	ENST00000443439.7	c.380G>C	p.Arg127Pro	missense_variant	2/19	1	NM_001040458.3	P1

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96341 AN: 151902 Hom.: 31278 Cov.: 31

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

GnomAD3 exomes AF: 0.637 AC: 160097 AN: 251238 Hom.: 52248 AF XY: 0.640 AC XY: 86937 AN XY: 135790

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 SAS exome AF: 0.549

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.: 74 AF XY: 0.686 AC XY: 498432 AN XY: 726916

Gnomad4 AFR exome AF: 0.514

Gnomad4 AMR exome AF: 0.562

Gnomad4 ASJ exome AF: 0.585

Gnomad4 EAS exome AF: 0.487

Gnomad4 SAS exome AF: 0.541

Gnomad4 FIN exome AF: 0.714

Gnomad4 NFE exome AF: 0.721

Gnomad4 OTH exome AF: 0.661

GnomAD4 genome AF: 0.634 AC: 96391 AN: 152020 Hom.: 31291 Cov.: 31 AF XY: 0.631 AC XY: 46906 AN XY: 74330

Gnomad4 AFR AF: 0.525

Gnomad4 AMR AF: 0.585

Gnomad4 ASJ AF: 0.577

Gnomad4 EAS AF: 0.485

Gnomad4 SAS AF: 0.546

Gnomad4 FIN AF: 0.719

Gnomad4 NFE AF: 0.720

Gnomad4 OTH AF: 0.621

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

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	1.8
Dann	Benign	0.65
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.070	T;T;T
MetaRNN	Benign	0.0000024	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.6	N;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.2	N;N;N
REVEL	Benign	0.044
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.082
MPC		0.11
ClinPred		0.0071	T
GERP RS		3.7
Varity_R		0.61
gMVP		0.59

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: rs26653; hg19: chr5-96139250; COSMIC: COSV57088163; COSMIC: COSV57088163;