5-96803761-C-T

Variant names:

• chr5-96803761-C-T
• rs3734016
• NM_001040458.3:c.166G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001040458.3(ERAP1):​c.166G>A​(p.Glu56Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0531 in 1,614,084 control chromosomes in the GnomAD database, including 3,224 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.059 (360 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2864 hom.)
• Consequence: ERAP1 NM_001040458.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0240
• Publications: 44 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]

ENSG00000272109 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018523037).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040458.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP1	NM_001040458.3	MANE Select	c.166G>A	p.Glu56Lys	missense	Exon 2 of 19	NP_001035548.1
	ERAP1	NM_001349244.2		c.166G>A	p.Glu56Lys	missense	Exon 2 of 20	NP_001336173.1
	ERAP1	NM_016442.5		c.166G>A	p.Glu56Lys	missense	Exon 2 of 20	NP_057526.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP1	ENST00000443439.7	TSL:1 MANE Select	c.166G>A	p.Glu56Lys	missense	Exon 2 of 19	ENSP00000406304.2
	ERAP1	ENST00000296754.7	TSL:1	c.166G>A	p.Glu56Lys	missense	Exon 2 of 20	ENSP00000296754.3
	ERAP1	ENST00000507154.1	TSL:3	c.166G>A	p.Glu56Lys	missense	Exon 3 of 3	ENSP00000421697.1

Frequencies

GnomAD3 genomes AF: 0.0588 AC: 8940 AN: 152088 Hom.: 356 Cov.: 32

Gnomad AFR AF: 0.0656

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0775

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.0574

Gnomad FIN AF: 0.0975

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0398

Gnomad OTH AF: 0.0426

GnomAD2 exomes AF: 0.0706 AC: 17749 AN: 251488 AF XY: 0.0650

Gnomad AFR exome AF: 0.0672

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.0261

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.0964

Gnomad NFE exome AF: 0.0394

Gnomad OTH exome AF: 0.0585

GnomAD4 exome AF: 0.0525 AC: 76685 AN: 1461878 Hom.: 2864 Cov.: 39 AF XY: 0.0515 AC XY: 37439 AN XY: 727238

African (AFR) AF: 0.0622 AC: 2082 AN: 33480

American (AMR) AF: 0.142 AC: 6337 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 664 AN: 26136

East Asian (EAS) AF: 0.180 AC: 7133 AN: 39698

South Asian (SAS) AF: 0.0498 AC: 4294 AN: 86258

European-Finnish (FIN) AF: 0.0964 AC: 5151 AN: 53414

Middle Eastern (MID) AF: 0.0153 AC: 88 AN: 5768

European-Non Finnish (NFE) AF: 0.0431 AC: 47875 AN: 1112004

Other (OTH) AF: 0.0507 AC: 3061 AN: 60396

GnomAD4 genome AF: 0.0588 AC: 8948 AN: 152206 Hom.: 360 Cov.: 32 AF XY: 0.0621 AC XY: 4619 AN XY: 74424

African (AFR) AF: 0.0655 AC: 2720 AN: 41522

American (AMR) AF: 0.0779 AC: 1192 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3470

East Asian (EAS) AF: 0.164 AC: 845 AN: 5166

South Asian (SAS) AF: 0.0568 AC: 274 AN: 4824

European-Finnish (FIN) AF: 0.0975 AC: 1033 AN: 10592

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0398 AC: 2706 AN: 68024

Other (OTH) AF: 0.0422 AC: 89 AN: 2110

Alfa AF: 0.0453 Hom.: 940

Bravo AF: 0.0588

TwinsUK AF: 0.0507 AC: 188

ALSPAC AF: 0.0420 AC: 162

ESP6500AA AF: 0.0588 AC: 259

ESP6500EA AF: 0.0398 AC: 342

ExAC AF: 0.0664 AC: 8061

Asia WGS AF: 0.116 AC: 404 AN: 3478

EpiCase AF: 0.0365

EpiControl AF: 0.0346

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.0083	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.54	N
PhyloP100		-0.024
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.043
Sift	Benign	0.71	T
Sift4G	Benign	0.91	T
Polyphen		0.0080	B
Vest4		0.083
MPC		0.083
ClinPred		0.0023	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.086
gMVP		0.73
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3734016; hg19: chr5-96139464; COSMIC: COSV57088546; COSMIC: COSV57088546;