rs4953354

chr2-46348249-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.217+1186A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,124 control chromosomes in the GnomAD database, including 3,966 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 0.22 (3966 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.162

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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPAS1	NM_001430.5	c.217+1186A>G		intron_variant		ENST00000263734.5
EPAS1	XM_011532698.3	c.256+1186A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPAS1	ENST00000263734.5	c.217+1186A>G		intron_variant		1	NM_001430.5	P1
EPAS1	ENST00000449347.5	c.217+1186A>G		intron_variant		3
EPAS1	ENST00000475822.1	n.408+1186A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33487 AN: 152006 Hom.: 3965 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.243

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

GnomAD4 genome AF: 0.220 AC: 33512 AN: 152124 Hom.: 3966 Cov.: 32 AF XY: 0.221 AC XY: 16423 AN XY: 74356

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.354

Gnomad4 EAS AF: 0.114

Gnomad4 SAS AF: 0.294

Gnomad4 FIN AF: 0.171

Gnomad4 NFE AF: 0.202

Gnomad4 OTH AF: 0.240

Alfa AF: 0.220 Hom.: 558

Bravo AF: 0.230

Asia WGS AF: 0.196 AC: 684 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.75
Dann	Benign	0.49

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: rs4953354; hg19: chr2-46575388;