rs144285538

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_022350.5(ERAP2):​c.114C>G​(p.Phe38Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000719 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00075 ( 0 hom. )

Consequence

ERAP2
NM_022350.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.69

Publications

3 publications found
Variant links:
Genes affected
ERAP2 (HGNC:29499): (endoplasmic reticulum aminopeptidase 2) This gene encodes a zinc metalloaminopeptidase of the M1 protease family that resides in the endoplasmic reticulum and functions in N-terminal trimming antigenic epitopes for presentation by major histocompatibility complex (MHC) class I molecules. Certain mutations in this gene are associated with the inflammatory arthritis syndrome ankylosing spondylitis and pre-eclampsia. This gene is located adjacent to a closely related aminopeptidase gene on chromosome 5. [provided by RefSeq, Jul 2016]
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: Likely_benign. The variant received -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.013260931).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERAP2NM_022350.5 linkc.114C>G p.Phe38Leu missense_variant Exon 2 of 19 ENST00000437043.8 NP_071745.1 Q6P179-1B2R769

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERAP2ENST00000437043.8 linkc.114C>G p.Phe38Leu missense_variant Exon 2 of 19 1 NM_022350.5 ENSP00000400376.3 Q6P179-1

Frequencies

GnomAD3 genomes
AF:
0.000460
AC:
70
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000705
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000350
AC:
88
AN:
251096
AF XY:
0.000339
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000666
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000520
Gnomad OTH exome
AF:
0.000490
GnomAD4 exome
AF:
0.000746
AC:
1091
AN:
1461838
Hom.:
0
Cov.:
31
AF XY:
0.000693
AC XY:
504
AN XY:
727216
show subpopulations
African (AFR)
AF:
0.000179
AC:
6
AN:
33480
American (AMR)
AF:
0.000492
AC:
22
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26134
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53408
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.000912
AC:
1014
AN:
1111988
Other (OTH)
AF:
0.000778
AC:
47
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.498
Heterozygous variant carriers
0
65
129
194
258
323
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
48
96
144
192
240
<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:
0.000460
AC:
70
AN:
152334
Hom.:
0
Cov.:
33
AF XY:
0.000470
AC XY:
35
AN XY:
74494
show subpopulations
African (AFR)
AF:
0.000144
AC:
6
AN:
41566
American (AMR)
AF:
0.00105
AC:
16
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000706
AC:
48
AN:
68036
Other (OTH)
AF:
0.00
AC:
0
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.510
Heterozygous variant carriers
0
4
7
11
14
18
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000714
Hom.:
0
Bravo
AF:
0.000465
TwinsUK
AF:
0.00243
AC:
9
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000930
AC:
8
ExAC
AF:
0.000305
AC:
37
EpiCase
AF:
0.000491
EpiControl
AF:
0.000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Apr 08, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.114C>G (p.F38L) alteration is located in exon 2 (coding exon 1) of the ERAP2 gene. This alteration results from a C to G substitution at nucleotide position 114, causing the phenylalanine (F) at amino acid position 38 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
8.9
DANN
Benign
0.75
DEOGEN2
Benign
0.0087
T;T;.;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.30
N
LIST_S2
Benign
0.57
T;T;T;T
M_CAP
Benign
0.0025
T
MetaRNN
Benign
0.013
T;T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.81
L;.;L;L
PhyloP100
1.7
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-0.39
N;N;N;N
REVEL
Benign
0.039
Sift
Benign
0.81
T;T;T;T
Sift4G
Benign
0.48
T;T;T;D
Polyphen
0.0
B;.;B;.
Vest4
0.16
MutPred
0.41
Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);
MVP
0.048
MPC
0.054
ClinPred
0.0046
T
GERP RS
2.2
PromoterAI
-0.0022
Neutral
Varity_R
0.045
gMVP
0.37
Mutation Taster
=93/7
polymorphism

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: rs144285538; hg19: chr5-96215503; API