5-96762191-T-G

Variant names:

• chr5-96762191-T-G
• rs27980
• ENST00000296754.7:c.*1009A>C

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.*1009A>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 0.353 in 756,206 control chromosomes in the GnomAD database, including 49,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10665 hom., cov: 32)
  • Exomes 𝑓: 0.35 (38794 hom.)
• Consequence: ERAP1 ENST00000296754.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.397
• Publications: 37 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=-0.87).
• BP6: Variant 5-96762191-T-G is Benign according to our data. Variant chr5-96762191-T-G is described in ClinVar as Benign. ClinVar VariationId is 1270230.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.1834-83T>G		intron_variant	Intron 24 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.1834-83T>G		intron_variant	Intron 24 of 31		NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55646 AN: 151950 Hom.: 10636 Cov.: 32

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.348

GnomAD4 exome AF: 0.349 AC: 211061 AN: 604134 Hom.: 38794 Cov.: 8 AF XY: 0.347 AC XY: 109239 AN XY: 314524

African (AFR) AF: 0.412 AC: 6001 AN: 14556

American (AMR) AF: 0.539 AC: 10116 AN: 18782

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 4488 AN: 15356

East Asian (EAS) AF: 0.589 AC: 17700 AN: 30066

South Asian (SAS) AF: 0.346 AC: 15048 AN: 43432

European-Finnish (FIN) AF: 0.373 AC: 16672 AN: 44748

Middle Eastern (MID) AF: 0.287 AC: 1049 AN: 3652

European-Non Finnish (NFE) AF: 0.322 AC: 129857 AN: 403594

Other (OTH) AF: 0.338 AC: 10130 AN: 29948

GnomAD4 genome AF: 0.366 AC: 55726 AN: 152072 Hom.: 10665 Cov.: 32 AF XY: 0.370 AC XY: 27536 AN XY: 74322

African (AFR) AF: 0.414 AC: 17174 AN: 41462

American (AMR) AF: 0.454 AC: 6926 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1035 AN: 3468

East Asian (EAS) AF: 0.513 AC: 2658 AN: 5184

South Asian (SAS) AF: 0.354 AC: 1707 AN: 4820

European-Finnish (FIN) AF: 0.358 AC: 3787 AN: 10572

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21419 AN: 67972

Other (OTH) AF: 0.348 AC: 737 AN: 2116

Alfa AF: 0.312 Hom.: 7001

Bravo AF: 0.375

Asia WGS AF: 0.453 AC: 1574 AN: 3476

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	-0.87
CADD	Benign	0.80
DANN	Benign	0.47
PhyloP100		-0.40
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: rs27980; hg19: chr5-96097895; COSMIC: COSV57090312;