rs4953342

Variant names:

• chr2-46324908-A-G
• rs4953342
• NM_001430.5:c.27-21965A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001430.5(EPAS1):​c.27-21965A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 152,226 control chromosomes in the GnomAD database, including 5,866 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 0.25 (5866 hom., cov: 34)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.533
• Publications: 5 publications found

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]

EPAS1 Gene-Disease associations (from GenCC):

• erythrocytosis, familial, 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• autosomal dominant secondary polycythemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001430.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	NM_001430.5	MANE Select	c.27-21965A>G		intron	N/A	NP_001421.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	ENST00000263734.5	TSL:1 MANE Select	c.27-21965A>G		intron	N/A	ENSP00000263734.3
	EPAS1	ENST00000449347.5	TSL:3	c.27-21965A>G		intron	N/A	ENSP00000406137.1
	EPAS1	ENST00000460015.1	TSL:4	n.433-21965A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38298 AN: 152108 Hom.: 5862 Cov.: 34

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.240

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

GnomAD4 genome AF: 0.252 AC: 38311 AN: 152226 Hom.: 5866 Cov.: 34 AF XY: 0.258 AC XY: 19207 AN XY: 74434

African (AFR) AF: 0.107 AC: 4446 AN: 41566

American (AMR) AF: 0.318 AC: 4866 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 755 AN: 3470

East Asian (EAS) AF: 0.648 AC: 3359 AN: 5180

South Asian (SAS) AF: 0.229 AC: 1106 AN: 4820

European-Finnish (FIN) AF: 0.383 AC: 4052 AN: 10578

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19041 AN: 68000

Other (OTH) AF: 0.245 AC: 518 AN: 2114

Alfa AF: 0.271 Hom.: 10870

Bravo AF: 0.247

Asia WGS AF: 0.444 AC: 1542 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.4
DANN	Benign	0.81
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4953342; hg19: chr2-46552047;