dbSNP rs11687512: EPAS1:c.26+24350G>C (chr2-46322287-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001430.5(EPAS1):c.26+24350G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0328 in 152,252 control chromosomes in the GnomAD database, including 139 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 0.033 ( 139 hom., cov: 32)

Consequence

EPAS1
NM_001430.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.22

Publications

4 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:

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=-0.73).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0328 (4993/152252) while in subpopulation NFE AF = 0.0475 (3231/68020). AF 95% confidence interval is 0.0461. There are 139 homozygotes in GnomAd4. There are 2560 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 4993 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPAS1	NM_001430.5 link	c.26+24350G>C		intron_variant	Intron 1 of 15	ENST00000263734.5	NP_001421.2	Q99814B3KW07
EPAS1	XM_011532698.3 link	c.-3525G>C		5_prime_UTR_variant	Exon 1 of 16		XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
EPAS1	ENST00000263734.5 link	c.26+24350G>C	intron_variant	Intron 1 of 15	1	NM_001430.5	ENSP00000263734.3	Q99814
EPAS1	ENST00000449347.5 link	c.26+24350G>C	intron_variant	Intron 2 of 6	3		ENSP00000406137.1	C9J9N2
EPAS1	ENST00000460015.1 link	n.433-24586G>C	intron_variant	Intron 1 of 1	4
EPAS1	ENST00000467888.5 link	n.174+24350G>C	intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.0328

AC:

4993

AN:

152134

Hom.:

139

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00751

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0151

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.0981

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0475

Gnomad OTH

AF:

0.0287

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0328

AC:

4993

AN:

152252

Hom.:

139

Cov.:

AF XY:

0.0344

AC XY:

2560

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00748

AC:

311

AN:

41556

American (AMR)

AF:

0.0150

AC:

230

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0118

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0981

AC:

1039

AN:

10594

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0475

AC:

3231

AN:

68020

Other (OTH)

AF:

0.0279

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

246

493

739

986

1232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0434

Hom.:

Bravo

AF:

0.0244

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

1.2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over