dbSNP rs10050860: ERAP1:p.Asp575His (chr5-96786506-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001040458.3(ERAP1):c.1723G>C(p.Asp575His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ERAP1
NM_001040458.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.527

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:

LOC124901031 (HGNC:):

LOC124901031 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09372443).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERAP1	NM_001040458.3 link	c.1723G>C	p.Asp575His	missense_variant	Exon 12 of 19	ENST00000443439.7	NP_001035548.1	Q9NZ08-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ERAP1	ENST00000443439.7 link	c.1723G>C	p.Asp575His	missense_variant	Exon 12 of 19	1	NM_001040458.3	ENSP00000406304.2	Q9NZ08-1
ERAP1	ENST00000296754.7 link	c.1723G>C	p.Asp575His	missense_variant	Exon 12 of 20	1		ENSP00000296754.3	Q9NZ08-2
ERAP1	ENST00000507859.1 link	n.386G>C		non_coding_transcript_exon_variant	Exon 4 of 5	2
ERAP1	ENST00000514604.5 link	n.147G>C		non_coding_transcript_exon_variant	Exon 2 of 6	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460116

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726468

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

.;T

Eigen

Benign

0.049

Eigen_PC

Benign

0.080

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.094

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.13

Sift

Benign

0.037

D;D

Sift4G

Uncertain

0.043

D;D

Polyphen

0.64

P;B

Vest4

0.28

MutPred

0.29

Loss of ubiquitination at K573 (P = 0.0528);Loss of ubiquitination at K573 (P = 0.0528);

MVP

0.22

MPC

0.092

ClinPred

0.75

GERP RS

5.3

Varity_R

0.14

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over