5-96762144-T-C

Variant summary

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

The ENST00000296754.7(ERAP1):c.*1056A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0835 in 484,834 control chromosomes in the GnomAD database, including 3,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.067 (745 hom., cov: 33)
  • Exomes 𝑓: 0.091 (2591 hom.)
• Consequence: ERAP1 ENST00000296754.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.363

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=-0.83).
• BP6: Variant 5-96762144-T-C is Benign according to our data. Variant chr5-96762144-T-C is described in ClinVar as [Benign]. Clinvar id is 1241023.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.1834-130T>C		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.1834-130T>C		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.0674 AC: 10253 AN: 152172 Hom.: 744 Cov.: 33

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.0583

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0579

Gnomad OTH AF: 0.0632

GnomAD4 exome AF: 0.0910 AC: 30252 AN: 332542 Hom.: 2591 Cov.: 4 AF XY: 0.0886 AC XY: 15248 AN XY: 172074

Gnomad4 AFR exome AF: 0.0153

Gnomad4 AMR exome AF: 0.241

Gnomad4 ASJ exome AF: 0.0318

Gnomad4 EAS exome AF: 0.335

Gnomad4 SAS exome AF: 0.0602

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.0576

Gnomad4 OTH exome AF: 0.0676

GnomAD4 genome AF: 0.0673 AC: 10255 AN: 152292 Hom.: 745 Cov.: 33 AF XY: 0.0726 AC XY: 5406 AN XY: 74476

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.0300

Gnomad4 EAS AF: 0.241

Gnomad4 SAS AF: 0.0576

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.0580

Gnomad4 OTH AF: 0.0620

Alfa AF: 0.0582 Hom.: 98

Bravo AF: 0.0726

Asia WGS AF: 0.139 AC: 481 AN: 3474

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	-0.83
Cadd	Benign	1.4
Dann	Benign	0.72

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: rs17086651; hg19: chr5-96097848;