rs27528

Variant names:

• chr5-96800822-T-C
• rs27528
• NM_001040458.3:c.663+40A>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.663+40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,609,316 control chromosomes in the GnomAD database, including 51,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5058 hom., cov: 32)
  • Exomes 𝑓: 0.25 (46856 hom.)
• Consequence: ERAP1 NM_001040458.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.290
• Publications: 10 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 (BayesDel_noAF=-0.88).
• BP6: Variant 5-96800822-T-C is Benign according to our data. Variant chr5-96800822-T-C is described in ClinVar as Benign. ClinVar VariationId is 2688414.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERAP1	NM_001040458.3	c.663+40A>G		intron_variant	Intron 3 of 18	ENST00000443439.7	NP_001035548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERAP1	ENST00000443439.7	c.663+40A>G		intron_variant	Intron 3 of 18	1	NM_001040458.3	ENSP00000406304.2
ERAP1	ENST00000296754.7	c.663+40A>G		intron_variant	Intron 3 of 19	1		ENSP00000296754.3
ERAP1	ENST00000503921.5	c.-61+2581A>G		intron_variant	Intron 2 of 2	4		ENSP00000427025.1
ERAP1	ENST00000508227.5	c.*112A>G		downstream_gene_variant		4		ENSP00000422631.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38642 AN: 152050 Hom.: 5051 Cov.: 32

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.244

GnomAD2 exomes AF: 0.272 AC: 68198 AN: 251024 AF XY: 0.268

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.413

Gnomad ASJ exome AF: 0.257

Gnomad EAS exome AF: 0.173

Gnomad FIN exome AF: 0.273

Gnomad NFE exome AF: 0.247

Gnomad OTH exome AF: 0.260

GnomAD4 exome AF: 0.251 AC: 365656 AN: 1457148 Hom.: 46856 Cov.: 30 AF XY: 0.252 AC XY: 182499 AN XY: 725208

African (AFR) AF: 0.247 AC: 8233 AN: 33390

American (AMR) AF: 0.403 AC: 18027 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 6632 AN: 26104

East Asian (EAS) AF: 0.210 AC: 8337 AN: 39646

South Asian (SAS) AF: 0.282 AC: 24256 AN: 86146

European-Finnish (FIN) AF: 0.273 AC: 14571 AN: 53350

Middle Eastern (MID) AF: 0.233 AC: 1339 AN: 5758

European-Non Finnish (NFE) AF: 0.243 AC: 269241 AN: 1107832

Other (OTH) AF: 0.249 AC: 15020 AN: 60214

GnomAD4 genome AF: 0.254 AC: 38675 AN: 152168 Hom.: 5058 Cov.: 32 AF XY: 0.258 AC XY: 19181 AN XY: 74386

African (AFR) AF: 0.245 AC: 10182 AN: 41514

American (AMR) AF: 0.325 AC: 4969 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 904 AN: 3468

East Asian (EAS) AF: 0.195 AC: 1008 AN: 5176

South Asian (SAS) AF: 0.295 AC: 1422 AN: 4820

European-Finnish (FIN) AF: 0.280 AC: 2958 AN: 10578

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16466 AN: 68010

Other (OTH) AF: 0.241 AC: 510 AN: 2112

Alfa AF: 0.252 Hom.: 907

Bravo AF: 0.259

Asia WGS AF: 0.232 AC: 812 AN: 3478

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 51% of patients studied by a panel of primary immunodeficiencies. Number of patients: 45. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.021
DANN	Benign	0.43
PhyloP100		-0.29
Mutation Taster		=100/0	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: rs27528; hg19: chr5-96136525; COSMIC: COSV57086483; COSMIC: COSV57086483;