chr5-96774507-A-T

Variant names:

• chr5-96774507-A-T
• rs7063
• NM_001040458.3:c.*1889T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001040458.3(ERAP1):​c.*1889T>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 0.287 in 984,688 control chromosomes in the GnomAD database, including 42,210 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 0.23 (4353 hom., cov: 32)
  • Exomes 𝑓: 0.30 (37857 hom.)
• Consequence: ERAP1 NM_001040458.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46
• Publications: 35 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040458.3. 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
	ERAP1	NM_001040458.3	MANE Select	c.*1889T>A		3_prime_UTR	Exon 19 of 19	NP_001035548.1	Q9NZ08-1
	CAST	NM_001750.7	MANE Select	c.*1891A>T		3_prime_UTR	Exon 32 of 32	NP_001741.4
	ERAP1	NM_001198541.3		c.*1889T>A		3_prime_UTR	Exon 19 of 19	NP_001185470.1	Q9NZ08-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP1	ENST00000443439.7	TSL:1 MANE Select	c.*1889T>A		3_prime_UTR	Exon 19 of 19	ENSP00000406304.2	Q9NZ08-1
	CAST	ENST00000675179.1	MANE Select	c.*1891A>T		3_prime_UTR	Exon 32 of 32	ENSP00000501872.1
	CAST	ENST00000309190.9	TSL:1	c.*1891A>T		3_prime_UTR	Exon 29 of 29	ENSP00000312523.5

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34238 AN: 152012 Hom.: 4350 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.0478

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.211

GnomAD4 exome AF: 0.298 AC: 248338 AN: 832558 Hom.: 37857 Cov.: 28 AF XY: 0.299 AC XY: 115056 AN XY: 384594

African (AFR) AF: 0.113 AC: 1776 AN: 15764

American (AMR) AF: 0.147 AC: 145 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 1386 AN: 5146

East Asian (EAS) AF: 0.0521 AC: 196 AN: 3764

South Asian (SAS) AF: 0.167 AC: 2752 AN: 16432

European-Finnish (FIN) AF: 0.265 AC: 374 AN: 1410

Middle Eastern (MID) AF: 0.271 AC: 438 AN: 1614

European-Non Finnish (NFE) AF: 0.308 AC: 234075 AN: 760186

Other (OTH) AF: 0.264 AC: 7196 AN: 27258

GnomAD4 genome AF: 0.225 AC: 34249 AN: 152130 Hom.: 4353 Cov.: 32 AF XY: 0.220 AC XY: 16381 AN XY: 74378

African (AFR) AF: 0.125 AC: 5200 AN: 41510

American (AMR) AF: 0.186 AC: 2851 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 885 AN: 3470

East Asian (EAS) AF: 0.0482 AC: 250 AN: 5192

South Asian (SAS) AF: 0.158 AC: 761 AN: 4828

European-Finnish (FIN) AF: 0.277 AC: 2926 AN: 10564

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.304 AC: 20667 AN: 67956

Other (OTH) AF: 0.212 AC: 448 AN: 2112

Alfa AF: 0.117 Hom.: 212

Bravo AF: 0.215

Asia WGS AF: 0.133 AC: 460 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.75
PhyloP100		1.5
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: rs7063; hg19: chr5-96110211;