chr5-96795133-T-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

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

Scores

3
15

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.636

Publications

88 publications found
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERAP1NM_001040458.3 linkc.828A>G p.Ile276Met missense_variant Exon 5 of 19 ENST00000443439.7 NP_001035548.1 Q9NZ08-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERAP1ENST00000443439.7 linkc.828A>G p.Ile276Met missense_variant Exon 5 of 19 1 NM_001040458.3 ENSP00000406304.2 Q9NZ08-1
ERAP1ENST00000296754.7 linkc.828A>G p.Ile276Met missense_variant Exon 5 of 20 1 ENSP00000296754.3 Q9NZ08-2

Frequencies

GnomAD3 genomes
AF:
0.223
AC:
33818
AN:
151870
Hom.:
3817
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.474
Heterozygous variant carriers
0
14013
28026
42040
56053
70066
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
8818
17636
26454
35272
44090
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.223
AC:
33837
AN:
151990
Hom.:
3818
Cov.:
32
AF XY:
0.222
AC XY:
16468
AN XY:
74306
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
1312
2624
3935
5247
6559
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
366
732
1098
1464
1830
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.234
Hom.:
20649
Bravo
AF:
0.215
TwinsUK
AF:
0.224
AC:
832
ALSPAC
AF:
0.233
AC:
898
ESP6500AA
AF:
0.202
AC:
889
ESP6500EA
AF:
0.228
AC:
1965
ExAC
AF:
0.227
AC:
27533
Asia WGS
AF:
0.270
AC:
940
AN:
3478
EpiCase
AF:
0.242
EpiControl
AF:
0.231

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

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 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 27. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN
Benign
0.0016
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.5
M;M
PhyloP100
-0.64
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.1
N;N
REVEL
Benign
0.18
Sift
Benign
0.063
T;T
Sift4G
Benign
0.076
T;T
Polyphen
0.73
P;P
Vest4
0.18
MPC
0.25
ClinPred
0.045
T
GERP RS
-0.18
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

Publications

Other links and lift over

dbSNP: rs26618; hg19: chr5-96130836; COSMIC: COSV57087450; COSMIC: COSV57087450; API