5-96783162-C-T

Position:

• chr5-96783162-C-T

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.2174G>A​(p.Arg725Gln) variant causes a missense change. The variant allele was found at a frequency of 0.189 in 1,613,990 control chromosomes in the GnomAD database, including 31,360 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 0.16 (2116 hom., cov: 33)
  • Exomes 𝑓: 0.19 (29244 hom.)
• Consequence: ERAP1 NM_001040458.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.74

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=0.0016841888).
• BP6: Variant 5-96783162-C-T is Benign according to our data. Variant chr5-96783162-C-T is described in ClinVar as [Benign]. Clinvar id is 2688505.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERAP1	NM_001040458.3	c.2174G>A	p.Arg725Gln	missense_variant	15/19	ENST00000443439.7	NP_001035548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERAP1	ENST00000443439.7	c.2174G>A	p.Arg725Gln	missense_variant	15/19	1	NM_001040458.3	ENSP00000406304.2
ERAP1	ENST00000296754.7	c.2174G>A	p.Arg725Gln	missense_variant	15/20	1		ENSP00000296754.3
ERAP1	ENST00000514604.5	n.598G>A		non_coding_transcript_exon_variant	5/6	5

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23586 AN: 152120 Hom.: 2114 Cov.: 33

Gnomad AFR AF: 0.0843

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0469

Gnomad SAS AF: 0.0872

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.150 AC: 37678 AN: 251358 Hom.: 3403 AF XY: 0.151 AC XY: 20561 AN XY: 135822

Gnomad AFR exome AF: 0.0852

Gnomad AMR exome AF: 0.0870

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.0487

Gnomad SAS exome AF: 0.0931

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.192 AC: 280983 AN: 1461752 Hom.: 29244 Cov.: 36 AF XY: 0.190 AC XY: 137974 AN XY: 727172

Gnomad4 AFR exome AF: 0.0824

Gnomad4 AMR exome AF: 0.0907

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.0449

Gnomad4 SAS exome AF: 0.0940

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.216

Gnomad4 OTH exome AF: 0.173

GnomAD4 genome AF: 0.155 AC: 23598 AN: 152238 Hom.: 2116 Cov.: 33 AF XY: 0.153 AC XY: 11386 AN XY: 74426

Gnomad4 AFR AF: 0.0841

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.0472

Gnomad4 SAS AF: 0.0881

Gnomad4 FIN AF: 0.202

Gnomad4 NFE AF: 0.211

Gnomad4 OTH AF: 0.134

Alfa AF: 0.183 Hom.: 4377

Bravo AF: 0.148

TwinsUK AF: 0.216 AC: 801

ALSPAC AF: 0.218 AC: 841

ESP6500AA AF: 0.0958 AC: 422

ESP6500EA AF: 0.205 AC: 1762

ExAC AF: 0.150 AC: 18224

Asia WGS AF: 0.0890 AC: 309 AN: 3478

EpiCase AF: 0.198

EpiControl AF: 0.199

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 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	.;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.15
Sift	Benign	0.13	T;T
Sift4G	Benign	0.084	T;T
Polyphen		0.76	P;P
Vest4		0.15
MPC		0.13
ClinPred		0.011	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17482078; hg19: chr5-96118866; COSMIC: COSV57087413; COSMIC: COSV57087413;