rs13391305

Variant names:

• chr2-46296782-T-C
• rs13391305
• ENST00000449347.5:c.-171+57T>C

Variant summary

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

The ENST00000449347.5(EPAS1):​c.-171+57T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0742 in 152,228 control chromosomes in the GnomAD database, including 1,265 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 0.074 (1265 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPAS1 ENST00000449347.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0550
• Publications: 1 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

ENSG00000304136 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000449347.5	c.-171+57T>C		intron_variant	Intron 1 of 6	3		ENSP00000406137.1
EPAS1	ENST00000460015.1	n.432+2684T>C		intron_variant	Intron 1 of 1	4
ENSG00000304136	ENST00000799986.1	n.118+352A>G		intron_variant	Intron 1 of 2
ENSG00000304136	ENST00000799987.1	n.42+352A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0741 AC: 11271 AN: 152110 Hom.: 1263 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0345

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00867

Gnomad SAS AF: 0.0531

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.0559

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 70 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 50

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 54

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.0742 AC: 11292 AN: 152228 Hom.: 1265 Cov.: 33 AF XY: 0.0728 AC XY: 5418 AN XY: 74452

African (AFR) AF: 0.244 AC: 10117 AN: 41476

American (AMR) AF: 0.0345 AC: 528 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00850 AC: 44 AN: 5176

South Asian (SAS) AF: 0.0528 AC: 255 AN: 4832

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00310 AC: 211 AN: 68028

Other (OTH) AF: 0.0553 AC: 117 AN: 2114

Alfa AF: 0.0436 Hom.: 77

Bravo AF: 0.0836

Asia WGS AF: 0.0570 AC: 196 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.8
DANN	Benign	0.43
PhyloP100		0.055
PromoterAI		0.15	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs13391305; hg19: chr2-46523921;