Genetic Variant ERAP1:p.Ser453Arg (chr5-96790605-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001040458.3(ERAP1):c.1359T>A(p.Ser453Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S453S) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ERAP1
NM_001040458.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.69

Publications

62 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]

ERAP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040458.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERAP1	NM_001040458.3	MANE Select	c.1359T>A	p.Ser453Arg	missense	Exon 9 of 19	NP_001035548.1	Q9NZ08-1
ERAP1	NM_001349244.2		c.1359T>A	p.Ser453Arg	missense	Exon 9 of 20	NP_001336173.1	Q9NZ08-2
ERAP1	NM_016442.5		c.1359T>A	p.Ser453Arg	missense	Exon 9 of 20	NP_057526.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERAP1	ENST00000443439.7	TSL:1 MANE Select	c.1359T>A	p.Ser453Arg	missense	Exon 9 of 19	ENSP00000406304.2	Q9NZ08-1
ERAP1	ENST00000296754.7	TSL:1	c.1359T>A	p.Ser453Arg	missense	Exon 9 of 20	ENSP00000296754.3	Q9NZ08-2
ERAP1	ENST00000853356.1		c.1359T>A	p.Ser453Arg	missense	Exon 9 of 19	ENSP00000523415.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1458876

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726038

African (AFR)

AF:

0.00

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109306

Other (OTH)

AF:

0.00

AC:

AN:

60284

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

97098

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.63

M_CAP

Benign

0.0074

MetaRNN

Uncertain

0.54

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PhyloP100

2.7

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.5

REVEL

Benign

0.092

Sift

Benign

0.14

Sift4G

Benign

0.56

Polyphen

0.019

Vest4

0.39

MutPred

0.68

Gain of solvent accessibility (P = 0.0171)

MVP

0.14

MPC

0.18

ClinPred

0.60

GERP RS

4.4

Varity_R

0.21

gMVP

0.62

Mutation Taster

=66/34

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over