rs7579899

Variant names:

• chr2-46310465-A-G
• rs7579899
• NM_001430.5:c.26+12528A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-46310465-A-G
• chr2-46310465-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001430.5(EPAS1):​c.26+12528A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 152,084 control chromosomes in the GnomAD database, including 21,338 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 0.51 (21338 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0880
• Publications: 44 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.26+12528A>G		intron_variant	Intron 1 of 15	ENST00000263734.5	NP_001421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.26+12528A>G		intron_variant	Intron 1 of 15	1	NM_001430.5	ENSP00000263734.3
EPAS1	ENST00000449347.5	c.26+12528A>G		intron_variant	Intron 2 of 6	3		ENSP00000406137.1
EPAS1	ENST00000460015.1	n.432+16367A>G		intron_variant	Intron 1 of 1	4
EPAS1	ENST00000467888.5	n.174+12528A>G		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78249 AN: 151966 Hom.: 21332 Cov.: 32

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.615

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.540

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

GnomAD4 genome AF: 0.515 AC: 78287 AN: 152084 Hom.: 21338 Cov.: 32 AF XY: 0.512 AC XY: 38070 AN XY: 74324

African (AFR) AF: 0.371 AC: 15384 AN: 41476

American (AMR) AF: 0.615 AC: 9401 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 2182 AN: 3466

East Asian (EAS) AF: 0.167 AC: 867 AN: 5186

South Asian (SAS) AF: 0.476 AC: 2294 AN: 4816

European-Finnish (FIN) AF: 0.542 AC: 5726 AN: 10564

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.597 AC: 40568 AN: 67978

Other (OTH) AF: 0.534 AC: 1127 AN: 2110

Alfa AF: 0.563 Hom.: 93219

Bravo AF: 0.508

Asia WGS AF: 0.317 AC: 1106 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.1
DANN	Benign	0.66
PhyloP100		0.088
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: rs7579899; hg19: chr2-46537604;