rs149173

Positions:

• chr5-96778789-T-C

Variant summary

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

The NM_001040458.3(ERAP1):​c.2670+1634A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 152,054 control chromosomes in the GnomAD database, including 4,379 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 0.22 (4379 hom., cov: 32)
• Consequence: ERAP1 NM_001040458.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.87

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERAP1	NM_001040458.3	c.2670+1634A>G		intron_variant		ENST00000443439.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERAP1	ENST00000443439.7	c.2670+1634A>G		intron_variant		1	NM_001040458.3	P1
ERAP1	ENST00000296754.7	c.2670+1634A>G		intron_variant		1
CAST	ENST00000510098.1	c.*438-533T>C		intron_variant, NMD_transcript_variant		1
ERAP1	ENST00000512852.1	c.206+1634A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33210 AN: 151936 Hom.: 4374 Cov.: 32

Gnomad AFR AF: 0.0787

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.237

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

GnomAD4 genome AF: 0.218 AC: 33216 AN: 152054 Hom.: 4379 Cov.: 32 AF XY: 0.224 AC XY: 16673 AN XY: 74322

Gnomad4 AFR AF: 0.0785

Gnomad4 AMR AF: 0.348

Gnomad4 ASJ AF: 0.262

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.306

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.234

Alfa AF: 0.212 Hom.: 1004

Bravo AF: 0.219

Asia WGS AF: 0.241 AC: 842 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.068
DANN	Benign	0.60

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: rs149173; hg19: chr5-96114493; COSMIC: COSV57086329; COSMIC: COSV57086329;