5-96783148-G-C

Variant names:

• chr5-96783148-G-C
• rs27044
• NM_001040458.3:c.2188C>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.2188C>G​(p.Gln730Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 1,613,816 control chromosomes in the GnomAD database, including 413,964 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 0.70 (37878 hom., cov: 32)
  • Exomes 𝑓: 0.72 (376086 hom.)
• Consequence: ERAP1 NM_001040458.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.778

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=1.956569E-5).
• BP6: Variant 5-96783148-G-C is Benign according to our data. Variant chr5-96783148-G-C is described in ClinVar as [Benign]. Clinvar id is 2688532.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERAP1	NM_001040458.3	c.2188C>G	p.Gln730Glu	missense_variant	Exon 15 of 19	ENST00000443439.7	NP_001035548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERAP1	ENST00000443439.7	c.2188C>G	p.Gln730Glu	missense_variant	Exon 15 of 19	1	NM_001040458.3	ENSP00000406304.2
ERAP1	ENST00000296754.7	c.2188C>G	p.Gln730Glu	missense_variant	Exon 15 of 20	1		ENSP00000296754.3
ERAP1	ENST00000514604.5	n.612C>G		non_coding_transcript_exon_variant	Exon 5 of 6	5

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106882 AN: 151950 Hom.: 37831 Cov.: 32

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.686

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.723

Gnomad OTH AF: 0.668

GnomAD3 exomes AF: 0.692 AC: 173885 AN: 251392 Hom.: 60690 AF XY: 0.696 AC XY: 94517 AN XY: 135858

Gnomad AFR exome AF: 0.717

Gnomad AMR exome AF: 0.659

Gnomad ASJ exome AF: 0.694

Gnomad EAS exome AF: 0.496

Gnomad SAS exome AF: 0.728

Gnomad FIN exome AF: 0.694

Gnomad NFE exome AF: 0.719

Gnomad OTH exome AF: 0.702

GnomAD4 exome AF: 0.716 AC: 1046529 AN: 1461746 Hom.: 376086 Cov.: 53 AF XY: 0.717 AC XY: 521283 AN XY: 727176

Gnomad4 AFR exome AF: 0.711

Gnomad4 AMR exome AF: 0.658

Gnomad4 ASJ exome AF: 0.697

Gnomad4 EAS exome AF: 0.560

Gnomad4 SAS exome AF: 0.719

Gnomad4 FIN exome AF: 0.695

Gnomad4 NFE exome AF: 0.726

Gnomad4 OTH exome AF: 0.704

GnomAD4 genome AF: 0.704 AC: 106982 AN: 152070 Hom.: 37878 Cov.: 32 AF XY: 0.701 AC XY: 52097 AN XY: 74336

Gnomad4 AFR AF: 0.711

Gnomad4 AMR AF: 0.663

Gnomad4 ASJ AF: 0.699

Gnomad4 EAS AF: 0.543

Gnomad4 SAS AF: 0.722

Gnomad4 FIN AF: 0.686

Gnomad4 NFE AF: 0.723

Gnomad4 OTH AF: 0.670

Alfa AF: 0.713 Hom.: 29211

Bravo AF: 0.698

TwinsUK AF: 0.731 AC: 2712

ALSPAC AF: 0.722 AC: 2783

ESP6500AA AF: 0.706 AC: 3111

ESP6500EA AF: 0.709 AC: 6094

ExAC AF: 0.694 AC: 84212

Asia WGS AF: 0.679 AC: 2360 AN: 3478

EpiCase AF: 0.730

EpiControl AF: 0.719

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 88% of patients studied by a panel of primary immunodeficiencies. Number of patients: 77. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.3
DANN	Benign	0.61
DEOGEN2	Benign	0.0089	.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.017	T;T
MetaRNN	Benign	0.000020	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.20	N;N
REVEL	Benign	0.069
Sift	Benign	0.62	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.038	B;B
Vest4		0.039
MPC		0.080
ClinPred		0.00030	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs27044; hg19: chr5-96118852; COSMIC: COSV57085400; COSMIC: COSV57085400;