chr5-96761124-A-G

Variant names:

• chr5-96761124-A-G
• rs13167972
• ENST00000296754.7:c.*2076T>C

Variant summary

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

The NM_016442.5(ERAP1):​c.*2076T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 152,022 control chromosomes in the GnomAD database, including 9,224 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 0.34 (9215 hom., cov: 32)
  • Exomes 𝑓: 0.35 (9 hom.)
• Consequence: ERAP1 NM_016442.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.78
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.39 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.1834-1150A>G		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.*2076T>C		3_prime_UTR	Exon 20 of 20	NP_001336173.1
	ERAP1	NM_016442.5		c.*2076T>C		3_prime_UTR	Exon 20 of 20	NP_057526.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP1	ENST00000296754.7	TSL:1	c.*2076T>C		3_prime_UTR	Exon 20 of 20	ENSP00000296754.3
	CAST	ENST00000675179.1	MANE Select	c.1834-1150A>G		intron	N/A	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.1585-1150A>G		intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52130 AN: 151766 Hom.: 9208 Cov.: 32

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.333

GnomAD4 exome AF: 0.353 AC: 48 AN: 136 Hom.: 9 Cov.: 0 AF XY: 0.392 AC XY: 29 AN XY: 74

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.353 AC: 48 AN: 136

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.343 AC: 52162 AN: 151886 Hom.: 9215 Cov.: 32 AF XY: 0.340 AC XY: 25201 AN XY: 74200

African (AFR) AF: 0.304 AC: 12624 AN: 41496

American (AMR) AF: 0.288 AC: 4407 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1412 AN: 3470

East Asian (EAS) AF: 0.107 AC: 555 AN: 5186

South Asian (SAS) AF: 0.350 AC: 1689 AN: 4822

European-Finnish (FIN) AF: 0.338 AC: 3570 AN: 10562

Middle Eastern (MID) AF: 0.375 AC: 108 AN: 288

European-Non Finnish (NFE) AF: 0.394 AC: 26671 AN: 67762

Other (OTH) AF: 0.334 AC: 706 AN: 2112

Alfa AF: 0.365 Hom.: 2555

Bravo AF: 0.336

Asia WGS AF: 0.249 AC: 855 AN: 3440

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.11
DANN	Benign	0.36
PhyloP100		-3.8
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: rs13167972; hg19: chr5-96096828;