rs27035

Variant names:

• chr5-96762440-G-A
• rs27035
• ENST00000296754.7:c.*760C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-96762440-G-A
• chr5-96762440-G-C
• chr5-96762440-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_016442.5(ERAP1):​c.*760C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,172,506 control chromosomes in the GnomAD database, including 154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (90 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (64 hom.)
• Consequence: ERAP1 NM_016442.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.46
• Publications: 2 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=-0.9).
• BP6: Variant 5-96762440-G-A is Benign according to our data. Variant chr5-96762440-G-A is described in ClinVar as Benign. ClinVar VariationId is 1242577.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0617 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+68G>A		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.*760C>T		3_prime_UTR	Exon 20 of 20	NP_001336173.1	Q9NZ08-2
	ERAP1	NM_016442.5		c.*760C>T		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.*760C>T		3_prime_UTR	Exon 20 of 20	ENSP00000296754.3	Q9NZ08-2
	CAST	ENST00000675179.1	MANE Select	c.1932+68G>A		intron	N/A	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.1683+68G>A		intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2807 AN: 152062 Hom.: 88 Cov.: 32

Gnomad AFR AF: 0.0635

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00675

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.00201 AC: 2054 AN: 1020326 Hom.: 64 Cov.: 13 AF XY: 0.00182 AC XY: 937 AN XY: 514460

African (AFR) AF: 0.0634 AC: 1421 AN: 22416

American (AMR) AF: 0.00350 AC: 79 AN: 22540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19018

East Asian (EAS) AF: 0.000115 AC: 4 AN: 34884

South Asian (SAS) AF: 0.00248 AC: 149 AN: 60040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48890

Middle Eastern (MID) AF: 0.00648 AC: 30 AN: 4628

European-Non Finnish (NFE) AF: 0.000194 AC: 148 AN: 763818

Other (OTH) AF: 0.00506 AC: 223 AN: 44092

GnomAD4 genome AF: 0.0186 AC: 2825 AN: 152180 Hom.: 90 Cov.: 32 AF XY: 0.0178 AC XY: 1323 AN XY: 74412

African (AFR) AF: 0.0637 AC: 2643 AN: 41488

American (AMR) AF: 0.00674 AC: 103 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68012

Other (OTH) AF: 0.0118 AC: 25 AN: 2110

Alfa AF: 0.00699 Hom.: 27

Bravo AF: 0.0214

Asia WGS AF: 0.00722 AC: 25 AN: 3478

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	-0.90
CADD	Benign	0.53
DANN	Benign	0.65
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs27035; hg19: chr5-96098144;