rs26618

Variant names:

• chr5-96795133-T-C
• rs26618
• NM_001040458.3:c.828A>G
• ERAP1 p.Ile276Met

Your query was ambiguous. Multiple possible variants found:

• chr5-96795133-T-C
• chr5-96795133-T-A
• chr5-96795133-T-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.828A>G​(p.Ile276Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,613,306 control chromosomes in the GnomAD database, including 43,473 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (3818 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39655 hom.)
• Consequence: ERAP1 NM_001040458.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.636
• Publications: 88 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=0.0016419888).
• BP6: Variant 5-96795133-T-C is Benign according to our data. Variant chr5-96795133-T-C is described in ClinVar as Benign. ClinVar VariationId is 2688460.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.258 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP1	NM_001040458.3	MANE Select	c.828A>G	p.Ile276Met	missense	Exon 5 of 19	NP_001035548.1	Q9NZ08-1
	ERAP1	NM_001349244.2		c.828A>G	p.Ile276Met	missense	Exon 5 of 20	NP_001336173.1	Q9NZ08-2
	ERAP1	NM_016442.5		c.828A>G	p.Ile276Met	missense	Exon 5 of 20	NP_057526.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP1	ENST00000443439.7	TSL:1 MANE Select	c.828A>G	p.Ile276Met	missense	Exon 5 of 19	ENSP00000406304.2	Q9NZ08-1
	ERAP1	ENST00000296754.7	TSL:1	c.828A>G	p.Ile276Met	missense	Exon 5 of 20	ENSP00000296754.3	Q9NZ08-2
	ERAP1	ENST00000853356.1		c.828A>G	p.Ile276Met	missense	Exon 5 of 19	ENSP00000523415.1

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33818 AN: 151870 Hom.: 3817 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.225

GnomAD2 exomes AF: 0.224 AC: 56187 AN: 250962 AF XY: 0.228

Gnomad AFR exome AF: 0.209

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.257

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.242

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.232 AC: 338850 AN: 1461316 Hom.: 39655 Cov.: 35 AF XY: 0.233 AC XY: 169062 AN XY: 726954

African (AFR) AF: 0.204 AC: 6813 AN: 33462

American (AMR) AF: 0.152 AC: 6800 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5092 AN: 26130

East Asian (EAS) AF: 0.260 AC: 10295 AN: 39672

South Asian (SAS) AF: 0.231 AC: 19888 AN: 86248

European-Finnish (FIN) AF: 0.231 AC: 12308 AN: 53250

Middle Eastern (MID) AF: 0.199 AC: 1145 AN: 5768

European-Non Finnish (NFE) AF: 0.236 AC: 262677 AN: 1111682

Other (OTH) AF: 0.229 AC: 13832 AN: 60390

GnomAD4 genome AF: 0.223 AC: 33837 AN: 151990 Hom.: 3818 Cov.: 32 AF XY: 0.222 AC XY: 16468 AN XY: 74306

African (AFR) AF: 0.207 AC: 8582 AN: 41448

American (AMR) AF: 0.183 AC: 2798 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 675 AN: 3472

East Asian (EAS) AF: 0.270 AC: 1387 AN: 5140

South Asian (SAS) AF: 0.234 AC: 1124 AN: 4812

European-Finnish (FIN) AF: 0.216 AC: 2283 AN: 10574

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.239 AC: 16263 AN: 67982

Other (OTH) AF: 0.227 AC: 480 AN: 2112

Alfa AF: 0.234 Hom.: 20649

Bravo AF: 0.215

Asia WGS AF: 0.270 AC: 940 AN: 3478

EpiCase AF: 0.242

EpiControl AF: 0.231

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.034
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.64
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.18
Sift	Benign	0.063	T
Sift4G	Benign	0.076	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.53
Mutation Taster		=87/13	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs26618;

hg19: chr5-96130836;

COSMIC: COSV57087450;

COSMIC: COSV57087450;