5-96786506-C-G

Variant names:

• chr5-96786506-C-G
• rs10050860
• NM_001040458.3:c.1723G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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. 14/22 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. D575N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ERAP1 NM_001040458.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.527
• Publications: 0 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]

LOC124901031 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09372443).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP1	NM_001040458.3	MANE Select	c.1723G>C	p.Asp575His	missense	Exon 12 of 19	NP_001035548.1	Q9NZ08-1
	ERAP1	NM_001349244.2		c.1723G>C	p.Asp575His	missense	Exon 12 of 20	NP_001336173.1	Q9NZ08-2
	ERAP1	NM_016442.5		c.1723G>C	p.Asp575His	missense	Exon 12 of 20	NP_057526.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP1	ENST00000443439.7	TSL:1 MANE Select	c.1723G>C	p.Asp575His	missense	Exon 12 of 19	ENSP00000406304.2	Q9NZ08-1
	ERAP1	ENST00000296754.7	TSL:1	c.1723G>C	p.Asp575His	missense	Exon 12 of 20	ENSP00000296754.3	Q9NZ08-2
	ERAP1	ENST00000853356.1		c.1723G>C	p.Asp575His	missense	Exon 12 of 19	ENSP00000523415.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460116 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726468

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44720

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: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5424

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110762

Other (OTH) AF: 0.00 AC: 0 AN: 60316

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T
Eigen	Benign	0.049
Eigen_PC	Benign	0.080
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.53
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.037	D
Sift4G	Uncertain	0.043	D
Polyphen		0.64	P
Vest4		0.28
MutPred		0.29		Loss of ubiquitination at K573 (P = 0.0528)
MVP		0.22
MPC		0.092
ClinPred		0.75	D
GERP RS		5.3
Varity_R		0.14
gMVP		0.55
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs10050860; hg19: chr5-96122210;