5-96783162-C-T

Variant names:

• chr5-96783162-C-T
• rs17482078
• NM_001040458.3:c.2174G>A

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.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 (★).

• 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
• Publications: 148 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=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 VariationId 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 rank	MANE	Protein	UniProt
ERAP1	NM_001040458.3	c.2174G>A	p.Arg725Gln	missense_variant	Exon 15 of 19	ENST00000443439.7	NP_001035548.1

Ensembl

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

GnomAD2 exomes AF: 0.150 AC: 37678 AN: 251358 AF XY: 0.151

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 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

African (AFR) AF: 0.0824 AC: 2758 AN: 33480

American (AMR) AF: 0.0907 AC: 4058 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 3323 AN: 26132

East Asian (EAS) AF: 0.0449 AC: 1781 AN: 39678

South Asian (SAS) AF: 0.0940 AC: 8110 AN: 86256

European-Finnish (FIN) AF: 0.191 AC: 10190 AN: 53414

Middle Eastern (MID) AF: 0.0976 AC: 563 AN: 5768

European-Non Finnish (NFE) AF: 0.216 AC: 239735 AN: 1111912

Other (OTH) AF: 0.173 AC: 10465 AN: 60392

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

African (AFR) AF: 0.0841 AC: 3494 AN: 41548

American (AMR) AF: 0.136 AC: 2077 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 434 AN: 3470

East Asian (EAS) AF: 0.0472 AC: 245 AN: 5186

South Asian (SAS) AF: 0.0881 AC: 426 AN: 4834

European-Finnish (FIN) AF: 0.202 AC: 2138 AN: 10586

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14365 AN: 67998

Other (OTH) AF: 0.134 AC: 284 AN: 2114

Alfa AF: 0.181 Hom.: 9254

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

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 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
PhyloP100		4.7
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17482078; hg19: chr5-96118866; COSMIC: COSV57087413; COSMIC: COSV57087413;