rs13160562

Positions:

• chr5-96775667-G-A

Variant summary

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

The NM_001040458.3(ERAP1):​c.*729C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 241,920 control chromosomes in the GnomAD database, including 8,782 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 (4344 hom., cov: 33)
  • Exomes 𝑓: 0.30 (4438 hom.)
• Consequence: ERAP1 NM_001040458.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.123

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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERAP1	NM_001040458.3	c.*729C>T		3_prime_UTR_variant	19/19	ENST00000443439.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERAP1	ENST00000443439.7	c.*729C>T		3_prime_UTR_variant	19/19	1	NM_001040458.3	P1
ERAP1	ENST00000296754.7	c.2818+737C>T		intron_variant		1
CAST	ENST00000510098.1	c.*351-1201G>A		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34189 AN: 152058 Hom.: 4341 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.0477

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.210

GnomAD4 exome AF: 0.302 AC: 27135 AN: 89744 Hom.: 4438 Cov.: 5 AF XY: 0.301 AC XY: 13117 AN XY: 43522

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.277

Gnomad4 EAS exome AF: 0.0455

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.423

Gnomad4 NFE exome AF: 0.312

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.225 AC: 34200 AN: 152176 Hom.: 4344 Cov.: 33 AF XY: 0.220 AC XY: 16354 AN XY: 74408

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.0480

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.277

Gnomad4 NFE AF: 0.303

Gnomad4 OTH AF: 0.211

Alfa AF: 0.275 Hom.: 3638

Bravo AF: 0.214

Asia WGS AF: 0.133 AC: 462 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.6
DANN	Benign	0.80

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: rs13160562; hg19: chr5-96111371;