5-96793832-T-C

Variant names:

• chr5-96793832-T-C
• rs2287987
• NM_001040458.3:c.1045A>G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERAP1	NM_001040458.3	c.1045A>G	p.Met349Val	missense_variant	Exon 6 of 19	ENST00000443439.7	NP_001035548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERAP1	ENST00000443439.7	c.1045A>G	p.Met349Val	missense_variant	Exon 6 of 19	1	NM_001040458.3	ENSP00000406304.2
ERAP1	ENST00000296754.7	c.1045A>G	p.Met349Val	missense_variant	Exon 6 of 20	1		ENSP00000296754.3
ERAP1	ENST00000503311.1	n.-161A>G		upstream_gene_variant		4

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

GnomAD3 exomes AF: 0.154 AC: 38690 AN: 250984 Hom.: 3577 AF XY: 0.156 AC XY: 21126 AN XY: 135660

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 SAS exome AF: 0.0965

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

Gnomad4 AFR exome AF: 0.0929

Gnomad4 AMR exome AF: 0.0931

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.0452

Gnomad4 SAS exome AF: 0.0974

Gnomad4 FIN exome AF: 0.193

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.178

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

Gnomad4 AFR AF: 0.0974

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.0472

Gnomad4 SAS AF: 0.0918

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.137

Alfa AF: 0.193 Hom.: 6355

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

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 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.072
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.20	B;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

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: rs2287987; hg19: chr5-96129535; COSMIC: COSV57085232; COSMIC: COSV57085232;