rs10515248

chr5-96776301-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001040458.3(ERAP1):c.*95G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,544,294 control chromosomes in the GnomAD database, including 10,911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.091 (827 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10084 hom.)
• Consequence: ERAP1 NM_001040458.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0390

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 5-96776301-C-T is Benign according to our data. Variant chr5-96776301-C-T is described in ClinVar as [Benign]. Clinvar id is 2688516.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERAP1	NM_001040458.3	c.*95G>A		3_prime_UTR_variant	19/19	ENST00000443439.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERAP1	ENST00000443439.7	c.*95G>A		3_prime_UTR_variant	19/19	1	NM_001040458.3	P1
ERAP1	ENST00000296754.7	c.2818+103G>A		intron_variant		1
CAST	ENST00000510098.1	c.*351-567C>T		intron_variant, NMD_transcript_variant		1
ERAP1	ENST00000512852.1	c.354+103G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0909 AC: 13823 AN: 152050 Hom.: 828 Cov.: 32

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0829

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.118

GnomAD4 exome AF: 0.116 AC: 161975 AN: 1392126 Hom.: 10084 Cov.: 34 AF XY: 0.116 AC XY: 79859 AN XY: 685950

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.0784

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.000796

Gnomad4 SAS exome AF: 0.0799

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.0908 AC: 13819 AN: 152168 Hom.: 827 Cov.: 32 AF XY: 0.0910 AC XY: 6771 AN XY: 74376

Gnomad4 AFR AF: 0.0220

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0832

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.117

Alfa AF: 0.124 Hom.: 1625

Bravo AF: 0.0865

Asia WGS AF: 0.0370 AC: 131 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 18. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	5.5
Dann	Benign	0.78

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: rs10515248; hg19: chr5-96112005; COSMIC: COSV57086928; COSMIC: COSV57086928;