dbSNP rs13428739: EPAS1:c.-171+70C>T (chr2-46296795-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000449347.5(EPAS1):c.-171+70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,230 control chromosomes in the GnomAD database, including 2,396 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 0.14 ( 2396 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EPAS1
ENST00000449347.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.829

Publications

8 publications found

Variant links:

Genes affected

EPAS1 (HGNC:3374): (endothelial PAS domain protein 1) This gene encodes a transcription factor involved in the induction of genes regulated by oxygen, which is induced as oxygen levels fall. The encoded protein contains a basic-helix-loop-helix domain protein dimerization domain as well as a domain found in proteins in signal transduction pathways which respond to oxygen levels. Mutations in this gene are associated with erythrocytosis familial type 4. [provided by RefSeq, Nov 2009]

EPAS1 Gene-Disease associations (from GenCC):

erythrocytosis, familial, 4
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
autosomal dominant secondary polycythemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EPAS1 links:

ENSG00000304136 (HGNC:):

ENSG00000304136 links:

Genome browser will be placed here

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=-0.87).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
EPAS1	ENST00000449347.5 link	c.-171+70C>T	intron_variant	Intron 1 of 6	3	ENSP00000406137.1	C9J9N2
EPAS1	ENST00000460015.1 link	n.432+2697C>T	intron_variant	Intron 1 of 1	4
ENSG00000304136	ENST00000799986.1 link	n.118+339G>A	intron_variant	Intron 1 of 2
ENSG00000304136	ENST00000799987.1 link	n.42+339G>A	intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.138

AC:

20946

AN:

152112

Hom.:

2374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.313

Gnomad AMI

AF:

0.129

Gnomad AMR

AF:

0.0839

Gnomad ASJ

AF:

0.0778

Gnomad EAS

AF:

0.0183

Gnomad SAS

AF:

0.0776

Gnomad FIN

AF:

0.0575

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0731

Gnomad OTH

AF:

0.116

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

AF XY:

0.00

AC XY:

AN XY:

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

GnomAD4 genome

AF:

0.138

AC:

21013

AN:

152230

Hom.:

2396

Cov.:

AF XY:

0.135

AC XY:

10066

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.314

AC:

13032

AN:

41480

American (AMR)

AF:

0.0838

AC:

1282

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0778

AC:

270

AN:

3470

East Asian (EAS)

AF:

0.0181

AC:

AN:

5180

South Asian (SAS)

AF:

0.0774

AC:

374

AN:

4830

European-Finnish (FIN)

AF:

0.0575

AC:

611

AN:

10626

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0731

AC:

4974

AN:

68018

Other (OTH)

AF:

0.114

AC:

242

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

838

1676

2514

3352

4190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

204

408

612

816

1020

<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.:

769

Bravo

AF:

0.148

Asia WGS

AF:

0.0840

AC:

293

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

5.0

(source)

DANN

Benign

0.89

PhyloP100

-0.83

PromoterAI

0.014

Neutral

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over