rs10050860

Positions:

• chr5-96786506-C-T

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.1723G>A​(p.Asp575Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,608,984 control chromosomes in the GnomAD database, including 33,580 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 same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D575G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2292 hom., cov: 33)
  • Exomes 𝑓: 0.20 (31288 hom.)
• Consequence: ERAP1 NM_001040458.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.527

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]

LOC124901031 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011562407).
• BP6: Variant 5-96786506-C-T is Benign according to our data. Variant chr5-96786506-C-T is described in ClinVar as [Benign]. Clinvar id is 2688495.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERAP1	NM_001040458.3	c.1723G>A	p.Asp575Asn	missense_variant	12/19	ENST00000443439.7	NP_001035548.1
LOC124901031	XR_007058877.1	n.2111C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERAP1	ENST00000443439.7	c.1723G>A	p.Asp575Asn	missense_variant	12/19	1	NM_001040458.3	ENSP00000406304	P1
ERAP1	ENST00000296754.7	c.1723G>A	p.Asp575Asn	missense_variant	12/20	1		ENSP00000296754
ERAP1	ENST00000507859.1	n.386G>A		non_coding_transcript_exon_variant	4/5	2
ERAP1	ENST00000514604.5	n.147G>A		non_coding_transcript_exon_variant	2/6	5

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24688 AN: 151994 Hom.: 2290 Cov.: 33

Gnomad AFR AF: 0.0952

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0470

Gnomad SAS AF: 0.0903

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.136

GnomAD3 exomes AF: 0.154 AC: 38756 AN: 251042 Hom.: 3589 AF XY: 0.156 AC XY: 21170 AN XY: 135682

Gnomad AFR exome AF: 0.0936

Gnomad AMR exome AF: 0.0899

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.0495

Gnomad SAS exome AF: 0.0963

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.209

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.198 AC: 289035 AN: 1456874 Hom.: 31288 Cov.: 31 AF XY: 0.196 AC XY: 141980 AN XY: 725024

Gnomad4 AFR exome AF: 0.0900

Gnomad4 AMR exome AF: 0.0938

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.0451

Gnomad4 SAS exome AF: 0.0972

Gnomad4 FIN exome AF: 0.193

Gnomad4 NFE exome AF: 0.223

Gnomad4 OTH exome AF: 0.179

GnomAD4 genome AF: 0.162 AC: 24704 AN: 152110 Hom.: 2292 Cov.: 33 AF XY: 0.160 AC XY: 11879 AN XY: 74362

Gnomad4 AFR AF: 0.0951

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.0473

Gnomad4 SAS AF: 0.0912

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.137

Alfa AF: 0.194 Hom.: 7592

Bravo AF: 0.155

TwinsUK AF: 0.226 AC: 839

ALSPAC AF: 0.228 AC: 877

ESP6500AA AF: 0.103 AC: 452

ESP6500EA AF: 0.213 AC: 1831

ExAC AF: 0.155 AC: 18792

Asia WGS AF: 0.0930 AC: 323 AN: 3478

EpiCase AF: 0.204

EpiControl AF: 0.205

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

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	0.066
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	17
DANN	Benign	0.75
DEOGEN2	Benign	0.016	.;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.33	T;T
MetaRNN	Benign	0.0012	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.57	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	1.0	N;N
REVEL	Benign	0.097
Sift	Benign	1.0	T;T
Sift4G	Benign	0.65	T;T
Polyphen		0.0	B;B
Vest4		0.037
MPC		0.072
ClinPred		0.0077	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.34

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: rs10050860; hg19: chr5-96122210; COSMIC: COSV57089586; COSMIC: COSV57089586;