ENST00000296754.7:c.*690C>T

Variant names:

• chr5-96762510-G-A
• rs27582
• ENST00000296754.7:c.*690C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 25 publications found

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]

CAST Gene-Disease associations (from GenCC):

• peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp

CAST (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.1932+138G>A		intron_variant	Intron 25 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.1932+138G>A		intron_variant	Intron 25 of 31		NM_001750.7	ENSP00000501872.1

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

African (AFR) AF: 0.429 AC: 4657 AN: 10866

American (AMR) AF: 0.513 AC: 6140 AN: 11970

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 3670 AN: 12272

East Asian (EAS) AF: 0.597 AC: 16891 AN: 28304

South Asian (SAS) AF: 0.369 AC: 10555 AN: 28614

European-Finnish (FIN) AF: 0.374 AC: 15665 AN: 41878

Middle Eastern (MID) AF: 0.284 AC: 964 AN: 3398

European-Non Finnish (NFE) AF: 0.327 AC: 80422 AN: 246274

Other (OTH) AF: 0.344 AC: 8037 AN: 23366

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

African (AFR) AF: 0.414 AC: 17165 AN: 41456

American (AMR) AF: 0.452 AC: 6899 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1035 AN: 3470

East Asian (EAS) AF: 0.512 AC: 2650 AN: 5178

South Asian (SAS) AF: 0.353 AC: 1701 AN: 4812

European-Finnish (FIN) AF: 0.358 AC: 3790 AN: 10572

Middle Eastern (MID) AF: 0.277 AC: 81 AN: 292

European-Non Finnish (NFE) AF: 0.315 AC: 21404 AN: 67992

Other (OTH) AF: 0.346 AC: 729 AN: 2108

Alfa AF: 0.336 Hom.: 11742

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

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.43
DANN	Benign	0.76
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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