rs13428739

Positions:

• chr2-46296795-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.829

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000449347.5	c.-171+70C>T		intron_variant		3		ENSP00000406137
EPAS1	ENST00000460015.1	n.432+2697C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20946 AN: 152112 Hom.: 2374 Cov.: 33

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: 0 AN: 54 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 36

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.138 AC: 21013 AN: 152230 Hom.: 2396 Cov.: 33 AF XY: 0.135 AC XY: 10066 AN XY: 74452

Gnomad4 AFR AF: 0.314

Gnomad4 AMR AF: 0.0838

Gnomad4 ASJ AF: 0.0778

Gnomad4 EAS AF: 0.0181

Gnomad4 SAS AF: 0.0774

Gnomad4 FIN AF: 0.0575

Gnomad4 NFE AF: 0.0731

Gnomad4 OTH AF: 0.114

Alfa AF: 0.102 Hom.: 431

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
DANN	Benign	0.89

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs13428739; hg19: chr2-46523934;