NM_001040458.3:c.1943+86T>C

Variant names:

• chr5-96785702-A-G
• rs469876
• NM_001040458.3:c.1943+86T>C

Variant summary

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

The NM_001040458.3(ERAP1):​c.1943+86T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,410,578 control chromosomes in the GnomAD database, including 38,087 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (3852 hom., cov: 33)
  • Exomes 𝑓: 0.23 (34235 hom.)
• Consequence: ERAP1 NM_001040458.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.897
• Publications: 14 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]

LOC124901031 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 5-96785702-A-G is Benign according to our data. Variant chr5-96785702-A-G is described in ClinVar as Benign. ClinVar VariationId is 2688459.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.249 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP1	NM_001040458.3	MANE Select	c.1943+86T>C		intron	N/A	NP_001035548.1
	ERAP1	NM_001349244.2		c.1943+86T>C		intron	N/A	NP_001336173.1
	ERAP1	NM_016442.5		c.1943+86T>C		intron	N/A	NP_057526.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP1	ENST00000443439.7	TSL:1 MANE Select	c.1943+86T>C		intron	N/A	ENSP00000406304.2
	ERAP1	ENST00000296754.7	TSL:1	c.1943+86T>C		intron	N/A	ENSP00000296754.3
	ERAP1	ENST00000507859.1	TSL:2	n.692T>C		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34000 AN: 152066 Hom.: 3850 Cov.: 33

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.223

GnomAD4 exome AF: 0.232 AC: 291705 AN: 1258394 Hom.: 34235 Cov.: 17 AF XY: 0.233 AC XY: 147063 AN XY: 632330

African (AFR) AF: 0.211 AC: 6162 AN: 29190

American (AMR) AF: 0.153 AC: 6048 AN: 39476

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 4694 AN: 24670

East Asian (EAS) AF: 0.254 AC: 9499 AN: 37426

South Asian (SAS) AF: 0.231 AC: 18215 AN: 78972

European-Finnish (FIN) AF: 0.231 AC: 11227 AN: 48572

Middle Eastern (MID) AF: 0.194 AC: 1047 AN: 5388

European-Non Finnish (NFE) AF: 0.237 AC: 222633 AN: 941150

Other (OTH) AF: 0.227 AC: 12180 AN: 53550

GnomAD4 genome AF: 0.224 AC: 34022 AN: 152184 Hom.: 3852 Cov.: 33 AF XY: 0.222 AC XY: 16552 AN XY: 74406

African (AFR) AF: 0.212 AC: 8797 AN: 41520

American (AMR) AF: 0.183 AC: 2802 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 664 AN: 3470

East Asian (EAS) AF: 0.261 AC: 1349 AN: 5176

South Asian (SAS) AF: 0.234 AC: 1126 AN: 4810

European-Finnish (FIN) AF: 0.215 AC: 2280 AN: 10582

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16278 AN: 68012

Other (OTH) AF: 0.225 AC: 477 AN: 2116

Alfa AF: 0.238 Hom.: 717

Bravo AF: 0.216

Asia WGS AF: 0.267 AC: 928 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 27. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.1
DANN	Benign	0.63
PhyloP100		0.90
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: rs469876; hg19: chr5-96121406;