rs1374749

chr2-46369294-G-Achr2-46369294-G-C

Variant summary

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

The NM_001430.5(EPAS1):c.780-533G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 151,966 control chromosomes in the GnomAD database, including 19,866 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 0.50 (19866 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.09

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 (EAS) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPAS1	NM_001430.5	c.780-533G>A		intron_variant		ENST00000263734.5
EPAS1	XM_011532698.3	c.819-533G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPAS1	ENST00000263734.5	c.780-533G>A		intron_variant		1	NM_001430.5	P1

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76559 AN: 151848 Hom.: 19825 Cov.: 32

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.636

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.811

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.512

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

GnomAD4 genome AF: 0.504 AC: 76650 AN: 151966 Hom.: 19866 Cov.: 32 AF XY: 0.514 AC XY: 38140 AN XY: 74266

Gnomad4 AFR AF: 0.488

Gnomad4 AMR AF: 0.637

Gnomad4 ASJ AF: 0.473

Gnomad4 EAS AF: 0.811

Gnomad4 SAS AF: 0.543

Gnomad4 FIN AF: 0.522

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.516

Alfa AF: 0.469 Hom.: 25196

Bravo AF: 0.512

Asia WGS AF: 0.645 AC: 2243 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	0.45
Dann	Benign	0.45

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: rs1374749; hg19: chr2-46596433;