rs3734016

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERAP1	NM_001040458.3	c.166G>A	p.Glu56Lys	missense_variant	Exon 2 of 19	ENST00000443439.7	NP_001035548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERAP1	ENST00000443439.7	c.166G>A	p.Glu56Lys	missense_variant	Exon 2 of 19	1	NM_001040458.3	ENSP00000406304.2

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

GnomAD3 exomes AF: 0.0706 AC: 17749 AN: 251488 Hom.: 958 AF XY: 0.0650 AC XY: 8828 AN XY: 135916

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 SAS exome AF: 0.0520

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

Gnomad4 AFR exome AF: 0.0622

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.0254

Gnomad4 EAS exome AF: 0.180

Gnomad4 SAS exome AF: 0.0498

Gnomad4 FIN exome AF: 0.0964

Gnomad4 NFE exome AF: 0.0431

Gnomad4 OTH exome AF: 0.0507

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

Gnomad4 AFR AF: 0.0655

Gnomad4 AMR AF: 0.0779

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.164

Gnomad4 SAS AF: 0.0568

Gnomad4 FIN AF: 0.0975

Gnomad4 NFE AF: 0.0398

Gnomad4 OTH AF: 0.0422

Alfa AF: 0.0428 Hom.: 437

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 v4.3

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;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.13	T;T;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.54	N;N;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.050	N;N;N
REVEL	Benign	0.043
Sift	Benign	0.71	T;T;T
Sift4G	Benign	0.91	T;T;T
Polyphen		0.0080	B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs3734016; hg19: chr5-96139464; COSMIC: COSV57088546; COSMIC: COSV57088546;