5-96880469-A-G

Variant names:

• chr5-96880469-A-G
• rs3733904
• NM_022350.5:c.575+209A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022350.5(ERAP2):​c.575+209A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 152,260 control chromosomes in the GnomAD database, including 2,284 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (2284 hom., cov: 33)
• Consequence: ERAP2 NM_022350.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 11 publications found

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]

ENSG00000247121 (HGNC:):

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022350.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP2	NM_022350.5	MANE Select	c.575+209A>G		intron	N/A	NP_071745.1
	ERAP2	NM_001130140.3		c.575+209A>G		intron	N/A	NP_001123612.1
	ERAP2	NM_001437802.1		c.575+209A>G		intron	N/A	NP_001424731.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP2	ENST00000437043.8	TSL:1 MANE Select	c.575+209A>G		intron	N/A	ENSP00000400376.3
	ERAP2	ENST00000379904.8	TSL:1	c.575+209A>G		intron	N/A	ENSP00000369235.4
	ERAP2	ENST00000510309.1	TSL:1	c.575+209A>G		intron	N/A	ENSP00000425758.1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23422 AN: 152142 Hom.: 2288 Cov.: 33

Gnomad AFR AF: 0.0478

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.0685

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.198

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.154 AC: 23412 AN: 152260 Hom.: 2284 Cov.: 33 AF XY: 0.153 AC XY: 11368 AN XY: 74434

African (AFR) AF: 0.0477 AC: 1984 AN: 41566

American (AMR) AF: 0.141 AC: 2150 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 958 AN: 3470

East Asian (EAS) AF: 0.0683 AC: 354 AN: 5184

South Asian (SAS) AF: 0.282 AC: 1363 AN: 4828

European-Finnish (FIN) AF: 0.169 AC: 1793 AN: 10592

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.207 AC: 14111 AN: 68010

Other (OTH) AF: 0.197 AC: 417 AN: 2114

Alfa AF: 0.197 Hom.: 5847

Bravo AF: 0.146

Asia WGS AF: 0.149 AC: 519 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.9
DANN	Benign	0.69
PhyloP100		1.1
PromoterAI		-0.022	Neutral
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs3733904; hg19: chr5-96216173;