NM_001040458.3:c.1045A>G

Variant names:

• chr5-96793832-T-C
• rs2287987
• NM_001040458.3:c.1045A>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.1045A>G​(p.Met349Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,612,274 control chromosomes in the GnomAD database, including 33,216 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2276 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30940 hom.)
• Consequence: ERAP1 NM_001040458.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.70
• Publications: 113 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=0.0017139018).
• BP6: Variant 5-96793832-T-C is Benign according to our data. Variant chr5-96793832-T-C is described in ClinVar as Benign. ClinVar VariationId is 2688496.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.215 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.1045A>G	p.Met349Val	missense	Exon 6 of 19	NP_001035548.1	Q9NZ08-1
	ERAP1	NM_001349244.2		c.1045A>G	p.Met349Val	missense	Exon 6 of 20	NP_001336173.1	Q9NZ08-2
	ERAP1	NM_016442.5		c.1045A>G	p.Met349Val	missense	Exon 6 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.1045A>G	p.Met349Val	missense	Exon 6 of 19	ENSP00000406304.2	Q9NZ08-1
	ERAP1	ENST00000296754.7	TSL:1	c.1045A>G	p.Met349Val	missense	Exon 6 of 20	ENSP00000296754.3	Q9NZ08-2
	ERAP1	ENST00000853356.1		c.1045A>G	p.Met349Val	missense	Exon 6 of 19	ENSP00000523415.1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24678 AN: 152128 Hom.: 2274 Cov.: 32

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0469

Gnomad SAS AF: 0.0909

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.154 AC: 38690 AN: 250984 AF XY: 0.156

Gnomad AFR exome AF: 0.0959

Gnomad AMR exome AF: 0.0894

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.0498

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.198 AC: 288576 AN: 1460028 Hom.: 30940 Cov.: 35 AF XY: 0.195 AC XY: 141730 AN XY: 726424

African (AFR) AF: 0.0929 AC: 3110 AN: 33468

American (AMR) AF: 0.0931 AC: 4164 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 3321 AN: 26120

East Asian (EAS) AF: 0.0452 AC: 1795 AN: 39684

South Asian (SAS) AF: 0.0974 AC: 8399 AN: 86240

European-Finnish (FIN) AF: 0.193 AC: 10303 AN: 53404

Middle Eastern (MID) AF: 0.0982 AC: 566 AN: 5766

European-Non Finnish (NFE) AF: 0.222 AC: 246172 AN: 1110300

Other (OTH) AF: 0.178 AC: 10746 AN: 60336

GnomAD4 genome AF: 0.162 AC: 24695 AN: 152246 Hom.: 2276 Cov.: 32 AF XY: 0.160 AC XY: 11899 AN XY: 74448

African (AFR) AF: 0.0974 AC: 4046 AN: 41552

American (AMR) AF: 0.139 AC: 2126 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 434 AN: 3472

East Asian (EAS) AF: 0.0472 AC: 245 AN: 5188

South Asian (SAS) AF: 0.0918 AC: 443 AN: 4828

European-Finnish (FIN) AF: 0.204 AC: 2158 AN: 10602

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14814 AN: 67990

Other (OTH) AF: 0.137 AC: 290 AN: 2112

Alfa AF: 0.186 Hom.: 9141

Bravo AF: 0.155

TwinsUK AF: 0.225 AC: 833

ALSPAC AF: 0.227 AC: 875

ESP6500AA AF: 0.105 AC: 462

ESP6500EA AF: 0.212 AC: 1822

ExAC AF: 0.154 AC: 18753

Asia WGS AF: 0.0930 AC: 323 AN: 3476

EpiCase AF: 0.203

EpiControl AF: 0.204

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	0.14
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.072
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.20	B
Vest4		0.18
MPC		0.13
ClinPred		0.0022	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.48
gMVP		0.52
Mutation Taster		=96/4	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: rs2287987; hg19: chr5-96129535; COSMIC: COSV57085232; COSMIC: COSV57085232;