Genetic Variant ERAP1:c.*95G>A (chr5-96776301-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001040458.3(ERAP1):c.*95G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,544,294 control chromosomes in the GnomAD database, including 10,911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.091 ( 827 hom., cov: 32)

Exomes 𝑓: 0.12 ( 10084 hom. )

Consequence

ERAP1
NM_001040458.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0390

Publications

18 publications found

Variant links:

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]

ERAP1 links:

CAST (HGNC:):

CAST links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 5-96776301-C-T is Benign according to our data. Variant chr5-96776301-C-T is described in ClinVar as Benign. ClinVar VariationId is 2688516.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERAP1	NM_001040458.3 link	c.*95G>A		3_prime_UTR_variant	Exon 19 of 19	ENST00000443439.7	NP_001035548.1	Q9NZ08-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ERAP1	ENST00000443439.7 link	c.*95G>A	3_prime_UTR_variant	Exon 19 of 19	1	NM_001040458.3	ENSP00000406304.2	Q9NZ08-1
ERAP1	ENST00000296754.7 link	c.2818+103G>A	intron_variant	Intron 19 of 19	1		ENSP00000296754.3	Q9NZ08-2
CAST	ENST00000510098.1 link	n.*351-567C>T	intron_variant	Intron 10 of 11	1		ENSP00000427195.1	A0A0C4DGD1
ERAP1	ENST00000512852.1 link	c.352+103G>A	intron_variant	Intron 3 of 3	3		ENSP00000425381.1	H0Y9X5

Frequencies

GnomAD3 genomes

AF:

0.0909

AC:

13823

AN:

152050

Hom.:

828

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0220

Gnomad AMI

AF:

0.151

Gnomad AMR

AF:

0.101

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0829

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.118

GnomAD4 exome

AF:

0.116

AC:

161975

AN:

1392126

Hom.:

10084

Cov.:

AF XY:

0.116

AC XY:

79859

AN XY:

685950

show subpopulations

African (AFR)

AF:

0.0192

AC:

597

AN:

31104

American (AMR)

AF:

0.0784

AC:

2753

AN:

35136

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

2592

AN:

22532

East Asian (EAS)

AF:

0.000796

AC:

AN:

38948

South Asian (SAS)

AF:

0.0799

AC:

5995

AN:

74990

European-Finnish (FIN)

AF:

0.118

AC:

5327

AN:

45132

Middle Eastern (MID)

AF:

0.114

AC:

618

AN:

5436

European-Non Finnish (NFE)

AF:

0.127

AC:

137650

AN:

1081328

Other (OTH)

AF:

0.111

AC:

6412

AN:

57520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

7319

14638

21956

29275

36594

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4930

9860

14790

19720

24650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0908

AC:

13819

AN:

152168

Hom.:

827

Cov.:

AF XY:

0.0910

AC XY:

6771

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0220

AC:

912

AN:

41536

American (AMR)

AF:

0.101

AC:

1537

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

407

AN:

3470

East Asian (EAS)

AF:

0.000773

AC:

AN:

5176

South Asian (SAS)

AF:

0.0832

AC:

400

AN:

4810

European-Finnish (FIN)

AF:

0.126

AC:

1337

AN:

10584

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.129

AC:

8791

AN:

67996

Other (OTH)

AF:

0.117

AC:

247

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

620

1240

1861

2481

3101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

328

492

656

820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.121

Hom.:

1976

Bravo

AF:

0.0865

Asia WGS

AF:

0.0370

AC:

131

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

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 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 18. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

5.5

(source)

DANN

Benign

0.78

PhyloP100

-0.039

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over