2-46331086-A-G

Variant names:

• chr2-46331086-A-G
• rs4953347
• NM_001430.5:c.27-15787A>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.27-15787A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 152,164 control chromosomes in the GnomAD database, including 35,939 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 0.66 (35939 hom., cov: 33)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.726
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.27-15787A>G		intron_variant	Intron 1 of 15	ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.65+5210A>G		intron_variant	Intron 1 of 15		XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.27-15787A>G		intron_variant	Intron 1 of 15	1	NM_001430.5	ENSP00000263734.3
EPAS1	ENST00000449347.5	c.27-15787A>G		intron_variant	Intron 2 of 6	3		ENSP00000406137.1
EPAS1	ENST00000460015.1	n.433-15787A>G		intron_variant	Intron 1 of 1	4
EPAS1	ENST00000467888.5	n.175-15787A>G		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.665 AC: 101059 AN: 152046 Hom.: 35883 Cov.: 33

Gnomad AFR AF: 0.898

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.969

Gnomad SAS AF: 0.614

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.616

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

GnomAD4 genome AF: 0.665 AC: 101177 AN: 152164 Hom.: 35939 Cov.: 33 AF XY: 0.669 AC XY: 49770 AN XY: 74374

African (AFR) AF: 0.898 AC: 37335 AN: 41560

American (AMR) AF: 0.715 AC: 10914 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1755 AN: 3470

East Asian (EAS) AF: 0.969 AC: 5023 AN: 5184

South Asian (SAS) AF: 0.613 AC: 2954 AN: 4822

European-Finnish (FIN) AF: 0.581 AC: 6135 AN: 10562

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.515 AC: 35019 AN: 67988

Other (OTH) AF: 0.619 AC: 1307 AN: 2110

Alfa AF: 0.545 Hom.: 18939

Bravo AF: 0.689

Asia WGS AF: 0.800 AC: 2781 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.5
DANN	Benign	0.64
PhyloP100		0.73
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: rs4953347; hg19: chr2-46558225;