ENST00000296754.7:c.*1056A>G

Variant names:

• chr5-96762144-T-C
• rs17086651
• ENST00000296754.7:c.*1056A>G

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.*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
• Publications: 7 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, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

CAST (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000296754.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.1834-130T>C		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.*1056A>G		3_prime_UTR	Exon 20 of 20	NP_001336173.1	Q9NZ08-2
	ERAP1	NM_016442.5		c.*1056A>G		3_prime_UTR	Exon 20 of 20	NP_057526.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP1	ENST00000296754.7	TSL:1	c.*1056A>G		3_prime_UTR	Exon 20 of 20	ENSP00000296754.3	Q9NZ08-2
	CAST	ENST00000675179.1	MANE Select	c.1834-130T>C		intron	N/A	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.1585-130T>C		intron	N/A	ENSP00000339914.3

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

African (AFR) AF: 0.0153 AC: 133 AN: 8672

American (AMR) AF: 0.241 AC: 2570 AN: 10680

Ashkenazi Jewish (ASJ) AF: 0.0318 AC: 342 AN: 10738

East Asian (EAS) AF: 0.335 AC: 8519 AN: 25426

South Asian (SAS) AF: 0.0602 AC: 977 AN: 16236

European-Finnish (FIN) AF: 0.125 AC: 4750 AN: 38000

Middle Eastern (MID) AF: 0.0145 AC: 24 AN: 1660

European-Non Finnish (NFE) AF: 0.0576 AC: 11614 AN: 201550

Other (OTH) AF: 0.0676 AC: 1323 AN: 19580

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

African (AFR) AF: 0.0143 AC: 593 AN: 41574

American (AMR) AF: 0.174 AC: 2663 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3470

East Asian (EAS) AF: 0.241 AC: 1253 AN: 5192

South Asian (SAS) AF: 0.0576 AC: 278 AN: 4830

European-Finnish (FIN) AF: 0.121 AC: 1280 AN: 10604

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0580 AC: 3942 AN: 68018

Other (OTH) AF: 0.0620 AC: 131 AN: 2112

Alfa AF: 0.0573 Hom.: 296

Bravo AF: 0.0726

Asia WGS AF: 0.139 AC: 481 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.72
PhyloP100		-0.36
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: rs17086651; hg19: chr5-96097848;