rs372831043

Variant names:

• chr5-96879701-G-A
• rs372831043
• NM_022350.5:c.16G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-96879701-G-A
• chr5-96879701-G-T

Variant summary

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

The NM_022350.5(ERAP2):​c.16G>A​(p.Ala6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ERAP2 NM_022350.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0130
• Publications: 0 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]

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]

ENSG00000247121 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.036000073).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP2	NM_022350.5	MANE Select	c.16G>A	p.Ala6Thr	missense	Exon 2 of 19	NP_071745.1	Q6P179-1
	ERAP2	NM_001130140.3		c.16G>A	p.Ala6Thr	missense	Exon 2 of 19	NP_001123612.1
	ERAP2	NM_001437802.1		c.16G>A	p.Ala6Thr	missense	Exon 2 of 18	NP_001424731.1	A0AAQ5BHS6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP2	ENST00000437043.8	TSL:1 MANE Select	c.16G>A	p.Ala6Thr	missense	Exon 2 of 19	ENSP00000400376.3	Q6P179-1
	ERAP2	ENST00000379904.8	TSL:1	c.16G>A	p.Ala6Thr	missense	Exon 2 of 18	ENSP00000369235.4	Q6P179-3
	ERAP2	ENST00000510309.1	TSL:1	c.16G>A	p.Ala6Thr	missense	Exon 1 of 4	ENSP00000425758.1	Q6P179-4

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250772 AF XY: 0.00000738

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461368 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726924

African (AFR) AF: 0.000239 AC: 8 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111586

Other (OTH) AF: 0.0000166 AC: 1 AN: 60376

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74330

African (AFR) AF: 0.000314 AC: 13 AN: 41452

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.7
DANN	Benign	0.96
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.013
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.025
Sift	Benign	0.23	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.093
MVP		0.061
MPC		0.046
ClinPred		0.060	T
GERP RS		1.5
PromoterAI		-0.0064	Neutral
Varity_R		0.027
gMVP		0.30
Mutation Taster		=97/3	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

Other links and lift over

dbSNP: rs372831043; hg19: chr5-96215405;