rs4953348

Positions:

• chr2-46331293-A-G

Variant summary

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

The NM_001430.5(EPAS1):​c.27-15580A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 152,076 control chromosomes in the GnomAD database, including 14,525 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 0.42 (14525 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0770

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=-0.69).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPAS1	NM_001430.5	c.27-15580A>G		intron_variant		ENST00000263734.5
EPAS1	XM_011532698.3	c.65+5417A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPAS1	ENST00000263734.5	c.27-15580A>G		intron_variant		1	NM_001430.5	P1
EPAS1	ENST00000449347.5	c.27-15580A>G		intron_variant		3
EPAS1	ENST00000460015.1	n.433-15580A>G		intron_variant, non_coding_transcript_variant		4
EPAS1	ENST00000467888.5	n.175-15580A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.421 AC: 64026 AN: 151958 Hom.: 14509 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.418

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

GnomAD4 genome AF: 0.421 AC: 64073 AN: 152076 Hom.: 14525 Cov.: 32 AF XY: 0.428 AC XY: 31843 AN XY: 74328

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.579

Gnomad4 ASJ AF: 0.412

Gnomad4 EAS AF: 0.671

Gnomad4 SAS AF: 0.443

Gnomad4 FIN AF: 0.505

Gnomad4 NFE AF: 0.455

Gnomad4 OTH AF: 0.422

Alfa AF: 0.444 Hom.: 3579

Bravo AF: 0.422

Asia WGS AF: 0.556 AC: 1932 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.0
DANN	Benign	0.86

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: rs4953348; hg19: chr2-46558432;