5-96762510-G-A

Variant summary

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

The ENST00000296754.7(ERAP1):c.*690C>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 0.363 in 558,992 control chromosomes in the GnomAD database, including 38,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10636 hom., cov: 33)
  • Exomes 𝑓: 0.36 (27872 hom.)
• Consequence: ERAP1 ENST00000296754.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.552

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=-0.9).
• BP6: Variant 5-96762510-G-A is Benign according to our data. Variant chr5-96762510-G-A is described in ClinVar as [Benign]. Clinvar id is 1179486.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.1932+138G>A		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.1932+138G>A		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55577 AN: 151932 Hom.: 10607 Cov.: 33

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.345

GnomAD4 exome AF: 0.361 AC: 147001 AN: 406942 Hom.: 27872 Cov.: 5 AF XY: 0.361 AC XY: 76289 AN XY: 211478

Gnomad4 AFR exome AF: 0.429

Gnomad4 AMR exome AF: 0.513

Gnomad4 ASJ exome AF: 0.299

Gnomad4 EAS exome AF: 0.597

Gnomad4 SAS exome AF: 0.369

Gnomad4 FIN exome AF: 0.374

Gnomad4 NFE exome AF: 0.327

Gnomad4 OTH exome AF: 0.344

GnomAD4 genome AF: 0.366 AC: 55656 AN: 152050 Hom.: 10636 Cov.: 33 AF XY: 0.370 AC XY: 27502 AN XY: 74320

Gnomad4 AFR AF: 0.414

Gnomad4 AMR AF: 0.452

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.512

Gnomad4 SAS AF: 0.353

Gnomad4 FIN AF: 0.358

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.346

Alfa AF: 0.331 Hom.: 8666

Bravo AF: 0.374

Asia WGS AF: 0.452 AC: 1573 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.43
Dann	Benign	0.76

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: rs27582; hg19: chr5-96098214; COSMIC: COSV104393610;