rs3822682

Variant names:

• chr5-96763054-C-T
• rs3822682
• ENST00000296754.7:c.*146G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016442.5(ERAP1):​c.*146G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0825 in 757,636 control chromosomes in the GnomAD database, including 3,133 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.093 (793 hom., cov: 32)
  • Exomes 𝑓: 0.080 (2340 hom.)
• Consequence: ERAP1 NM_016442.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.218
• Publications: 5 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, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

CAST (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016442.5. 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.1932+682C>T		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.*146G>A		3_prime_UTR	Exon 20 of 20	NP_001336173.1	Q9NZ08-2
	ERAP1	NM_016442.5		c.*146G>A		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.*146G>A		3_prime_UTR	Exon 20 of 20	ENSP00000296754.3	Q9NZ08-2
	CAST	ENST00000675179.1	MANE Select	c.1932+682C>T		intron	N/A	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.1683+682C>T		intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes AF: 0.0933 AC: 14191 AN: 152096 Hom.: 794 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.0701

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0264

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.0405

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0730

Gnomad OTH AF: 0.100

GnomAD4 exome AF: 0.0798 AC: 48340 AN: 605422 Hom.: 2340 Cov.: 0 AF XY: 0.0834 AC XY: 27563 AN XY: 330650

African (AFR) AF: 0.147 AC: 2563 AN: 17386

American (AMR) AF: 0.0504 AC: 2156 AN: 42802

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 2936 AN: 20588

East Asian (EAS) AF: 0.0438 AC: 1564 AN: 35700

South Asian (SAS) AF: 0.134 AC: 9136 AN: 68068

European-Finnish (FIN) AF: 0.0430 AC: 1848 AN: 42958

Middle Eastern (MID) AF: 0.140 AC: 417 AN: 2980

European-Non Finnish (NFE) AF: 0.0727 AC: 24900 AN: 342650

Other (OTH) AF: 0.0873 AC: 2820 AN: 32290

GnomAD4 genome AF: 0.0933 AC: 14202 AN: 152214 Hom.: 793 Cov.: 32 AF XY: 0.0933 AC XY: 6944 AN XY: 74428

African (AFR) AF: 0.144 AC: 5973 AN: 41544

American (AMR) AF: 0.0700 AC: 1070 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 488 AN: 3466

East Asian (EAS) AF: 0.0264 AC: 137 AN: 5180

South Asian (SAS) AF: 0.136 AC: 655 AN: 4822

European-Finnish (FIN) AF: 0.0405 AC: 429 AN: 10602

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0731 AC: 4967 AN: 67994

Other (OTH) AF: 0.101 AC: 214 AN: 2114

Alfa AF: 0.0831 Hom.: 172

Bravo AF: 0.0964

Asia WGS AF: 0.0870 AC: 302 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.3
DANN	Benign	0.57
PhyloP100		0.22
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: rs3822682; hg19: chr5-96098758;