rs27639

Positions:

• chr5-96777338-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001040458.3(ERAP1):​c.2671-787T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 152,174 control chromosomes in the GnomAD database, including 1,653 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 0.13 (1653 hom., cov: 32)
• Consequence: ERAP1 NM_001040458.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.633

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]

CAST (HGNC:1515): (calpastatin) The protein encoded by this gene is an endogenous calpain (calcium-dependent cysteine protease) inhibitor. It consists of an N-terminal domain L and four repetitive calpain-inhibition domains (domains 1-4), and it is involved in the proteolysis of amyloid precursor protein. The calpain/calpastatin system is involved in numerous membrane fusion events, such as neural vesicle exocytosis and platelet and red-cell aggregation. The encoded protein is also thought to affect the expression levels of genes encoding structural or regulatory proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERAP1	NM_001040458.3	c.2671-787T>C		intron_variant		ENST00000443439.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERAP1	ENST00000443439.7	c.2671-787T>C		intron_variant		1	NM_001040458.3	P1
ERAP1	ENST00000296754.7	c.2671-787T>C		intron_variant		1
CAST	ENST00000510098.1	c.*437+384A>G		intron_variant, NMD_transcript_variant		1
ERAP1	ENST00000512852.1	c.207-787T>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19373 AN: 152056 Hom.: 1647 Cov.: 32

Gnomad AFR AF: 0.0565

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.118

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

GnomAD4 genome AF: 0.127 AC: 19383 AN: 152174 Hom.: 1653 Cov.: 32 AF XY: 0.133 AC XY: 9895 AN XY: 74394

Gnomad4 AFR AF: 0.0565

Gnomad4 AMR AF: 0.247

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.252

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.124

Gnomad4 OTH AF: 0.116

Alfa AF: 0.131 Hom.: 1507

Bravo AF: 0.133

Asia WGS AF: 0.208 AC: 724 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.2
DANN	Benign	0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs27639; hg19: chr5-96113042; COSMIC: COSV57086318; COSMIC: COSV57086318;