Genetic Variant NM_001040458.3:c.1525-65T>C (chr5-96788750-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001040458.3(ERAP1):c.1525-65T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,577,132 control chromosomes in the GnomAD database, including 11,321 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.092 ( 843 hom., cov: 32)

Exomes 𝑓: 0.12 ( 10478 hom. )

Consequence

ERAP1
NM_001040458.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0460

Publications

9 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERAP1	NM_001040458.3	MANE Select	c.1525-65T>C	intron	N/A	NP_001035548.1	Q9NZ08-1
ERAP1	NM_001349244.2		c.1525-65T>C	intron	N/A	NP_001336173.1	Q9NZ08-2
ERAP1	NM_016442.5		c.1525-65T>C	intron	N/A	NP_057526.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERAP1	ENST00000443439.7	TSL:1 MANE Select	c.1525-65T>C	intron	N/A	ENSP00000406304.2	Q9NZ08-1
ERAP1	ENST00000296754.7	TSL:1	c.1525-65T>C	intron	N/A	ENSP00000296754.3	Q9NZ08-2
ERAP1	ENST00000853356.1		c.1525-65T>C	intron	N/A	ENSP00000523415.1

Frequencies

GnomAD3 genomes

AF:

0.0917

AC:

13938

AN:

152066

Hom.:

844

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0221

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.126

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0839

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.130

Gnomad OTH

AF:

0.120

GnomAD4 exome

AF:

0.117

AC:

166595

AN:

1424948

Hom.:

10478

AF XY:

0.117

AC XY:

82640

AN XY:

707056

show subpopulations

African (AFR)

AF:

0.0198

AC:

648

AN:

32782

American (AMR)

AF:

0.0800

AC:

3261

AN:

40784

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

3302

AN:

25788

East Asian (EAS)

AF:

0.000755

AC:

AN:

38406

South Asian (SAS)

AF:

0.0825

AC:

6881

AN:

83356

European-Finnish (FIN)

AF:

0.121

AC:

5298

AN:

43928

Middle Eastern (MID)

AF:

0.113

AC:

650

AN:

5732

European-Non Finnish (NFE)

AF:

0.128

AC:

139856

AN:

1094944

Other (OTH)

AF:

0.113

AC:

6670

AN:

59228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

8086

16172

24258

32344

40430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4916

9832

14748

19664

24580

<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:

0.0916

AC:

13934

AN:

152184

Hom.:

843

Cov.:

AF XY:

0.0916

AC XY:

6812

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0221

AC:

916

AN:

41526

American (AMR)

AF:

0.103

AC:

1573

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.126

AC:

438

AN:

3470

East Asian (EAS)

AF:

0.000772

AC:

AN:

5180

South Asian (SAS)

AF:

0.0841

AC:

405

AN:

4814

European-Finnish (FIN)

AF:

0.126

AC:

1334

AN:

10584

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.130

AC:

8808

AN:

67994

Other (OTH)

AF:

0.119

AC:

251

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

633

1267

1900

2534

3167

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:

0.103

Hom.:

114

Bravo

AF:

0.0876

Asia WGS

AF:

0.0340

AC:

119

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

6.0

(source)

DANN

Benign

0.54

PhyloP100

-0.046

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over