5-96762440-G-A

Variant names:

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

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]

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.1932+68G>A		intron_variant	Intron 25 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.1932+68G>A		intron_variant	Intron 25 of 31		NM_001750.7	ENSP00000501872.1

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

Gnomad4 AFR exome AF: 0.0634 AC: 1421 AN: 22416

Gnomad4 AMR exome AF: 0.00350 AC: 79 AN: 22540

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19018

Gnomad4 EAS exome AF: 0.000115 AC: 4 AN: 34884

Gnomad4 SAS exome AF: 0.00248 AC: 149 AN: 60040

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 48890

Gnomad4 NFE exome AF: 0.000194 AC: 148 AN: 763818

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.0637 AC: 0.0637052 AN: 0.0637052

Gnomad4 AMR AF: 0.00674 AC: 0.00674437 AN: 0.00674437

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000578 AC: 0.000578035 AN: 0.000578035

Gnomad4 SAS AF: 0.00270 AC: 0.0026971 AN: 0.0026971

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000485 AC: 0.000485208 AN: 0.000485208

Gnomad4 OTH AF: 0.0118 AC: 0.0118483 AN: 0.0118483

Alfa AF: 0.00699 Hom.: 27

Bravo AF: 0.0214

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2021

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	-0.90
CADD	Benign	0.53
DANN	Benign	0.65
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

Publications

LitVar

Other links and lift over

dbSNP: rs27035; hg19: chr5-96098144;