rs1868085

Positions:

• chr2-46352519-G-A

Variant summary

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

The NM_001430.5(EPAS1):​c.218-3632G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 152,006 control chromosomes in the GnomAD database, including 4,222 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 0.23 (4222 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.80

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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.218-3632G>A		intron_variant		ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.257-3632G>A		intron_variant			XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.218-3632G>A		intron_variant		1	NM_001430.5	ENSP00000263734	P1
EPAS1	ENST00000449347.5	c.218-3632G>A		intron_variant		3		ENSP00000406137
EPAS1	ENST00000475822.1	n.409-3632G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34478 AN: 151888 Hom.: 4219 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.0995

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.236

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

GnomAD4 genome AF: 0.227 AC: 34497 AN: 152006 Hom.: 4222 Cov.: 32 AF XY: 0.231 AC XY: 17145 AN XY: 74322

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.308

Gnomad4 ASJ AF: 0.329

Gnomad4 EAS AF: 0.0998

Gnomad4 SAS AF: 0.293

Gnomad4 FIN AF: 0.244

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.233

Alfa AF: 0.240 Hom.: 1216

Bravo AF: 0.229

Asia WGS AF: 0.189 AC: 661 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.017
DANN	Benign	0.82

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

LitVar

Other links and lift over

dbSNP: rs1868085; hg19: chr2-46579658;