5-96762191-T-G

Variant summary

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

The ENST00000296754.7(ERAP1):c.*1009A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 756,206 control chromosomes in the GnomAD database, including 49,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10665 hom., cov: 32)
  • Exomes 𝑓: 0.35 (38794 hom.)
• Consequence: ERAP1 ENST00000296754.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.397

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=-0.87).
• BP6: Variant 5-96762191-T-G is Benign according to our data. Variant chr5-96762191-T-G is described in ClinVar as [Benign]. Clinvar id is 1270230.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.1834-83T>G		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.1834-83T>G		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55646 AN: 151950 Hom.: 10636 Cov.: 32

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.348

GnomAD4 exome AF: 0.349 AC: 211061 AN: 604134 Hom.: 38794 Cov.: 8 AF XY: 0.347 AC XY: 109239 AN XY: 314524

Gnomad4 AFR exome AF: 0.412

Gnomad4 AMR exome AF: 0.539

Gnomad4 ASJ exome AF: 0.292

Gnomad4 EAS exome AF: 0.589

Gnomad4 SAS exome AF: 0.346

Gnomad4 FIN exome AF: 0.373

Gnomad4 NFE exome AF: 0.322

Gnomad4 OTH exome AF: 0.338

GnomAD4 genome AF: 0.366 AC: 55726 AN: 152072 Hom.: 10665 Cov.: 32 AF XY: 0.370 AC XY: 27536 AN XY: 74322

Gnomad4 AFR AF: 0.414

Gnomad4 AMR AF: 0.454

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.513

Gnomad4 SAS AF: 0.354

Gnomad4 FIN AF: 0.358

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.348

Alfa AF: 0.308 Hom.: 5917

Bravo AF: 0.375

Asia WGS AF: 0.453 AC: 1574 AN: 3476

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	-0.87
Cadd	Benign	0.80
Dann	Benign	0.47

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: rs27980; hg19: chr5-96097895; COSMIC: COSV57090312;