rs149481

chr5-96778642-A-Cchr5-96778642-A-T

Variant summary

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

The NM_001040458.3(ERAP1):c.2670+1781T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 152,036 control chromosomes in the GnomAD database, including 9,141 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 0.34 (9141 hom., cov: 32)
• Consequence: ERAP1 NM_001040458.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00200

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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERAP1	NM_001040458.3	c.2670+1781T>G		intron_variant		ENST00000443439.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERAP1	ENST00000443439.7	c.2670+1781T>G		intron_variant		1	NM_001040458.3	P1
ERAP1	ENST00000296754.7	c.2670+1781T>G		intron_variant		1
CAST	ENST00000510098.1	c.*438-680A>C		intron_variant, NMD_transcript_variant		1
ERAP1	ENST00000512852.1	c.206+1781T>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51434 AN: 151916 Hom.: 9125 Cov.: 32

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.339

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

GnomAD4 genome AF: 0.339 AC: 51499 AN: 152036 Hom.: 9141 Cov.: 32 AF XY: 0.338 AC XY: 25134 AN XY: 74350

Gnomad4 AFR AF: 0.451

Gnomad4 AMR AF: 0.321

Gnomad4 ASJ AF: 0.309

Gnomad4 EAS AF: 0.290

Gnomad4 SAS AF: 0.331

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.293

Gnomad4 OTH AF: 0.343

Alfa AF: 0.295 Hom.: 9580

Bravo AF: 0.346

Asia WGS AF: 0.347 AC: 1205 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	4.5
Dann	Benign	0.88

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: rs149481; hg19: chr5-96114346;