5-96793840-C-A

Variant names:

• chr5-96793840-C-A
• rs27895
• NM_001040458.3:c.1037G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001040458.3(ERAP1):​c.1037G>T​(p.Gly346Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G346D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ERAP1 NM_001040458.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.526
• Publications: 35 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38269854).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP1	NM_001040458.3	MANE Select	c.1037G>T	p.Gly346Val	missense	Exon 6 of 19	NP_001035548.1
	ERAP1	NM_001349244.2		c.1037G>T	p.Gly346Val	missense	Exon 6 of 20	NP_001336173.1
	ERAP1	NM_016442.5		c.1037G>T	p.Gly346Val	missense	Exon 6 of 20	NP_057526.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP1	ENST00000443439.7	TSL:1 MANE Select	c.1037G>T	p.Gly346Val	missense	Exon 6 of 19	ENSP00000406304.2
	ERAP1	ENST00000296754.7	TSL:1	c.1037G>T	p.Gly346Val	missense	Exon 6 of 20	ENSP00000296754.3
	ERAP1	ENST00000503311.1	TSL:4	n.-169G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 1423

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.59
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.53
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.078
Sift	Benign	0.51	T
Sift4G	Benign	0.49	T
Polyphen		0.082	B
Vest4		0.22
MutPred		0.59		Loss of disorder (P = 0.0371)
MVP		0.076
MPC		0.20
ClinPred		0.17	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.69
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs27895; hg19: chr5-96129543;