NM_001430.5:c.27-15804T>G

Variant names:

• chr2-46331069-T-G
• rs4953346
• NM_001430.5:c.27-15804T>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.27-15804T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 152,086 control chromosomes in the GnomAD database, including 14,099 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 0.41 (14099 hom., cov: 33)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.939
• Publications: 6 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 = 0.655 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.27-15804T>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.27-15804T>G		intron	N/A	ENSP00000263734.3
	EPAS1	ENST00000861819.1		c.27-15804T>G		intron	N/A	ENSP00000531878.1
	EPAS1	ENST00000861817.1		c.27-15810T>G		intron	N/A	ENSP00000531876.1

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62241 AN: 151968 Hom.: 14085 Cov.: 33

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.411

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

GnomAD4 genome AF: 0.409 AC: 62278 AN: 152086 Hom.: 14099 Cov.: 33 AF XY: 0.417 AC XY: 31006 AN XY: 74330

African (AFR) AF: 0.213 AC: 8846 AN: 41502

American (AMR) AF: 0.574 AC: 8766 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 1431 AN: 3472

East Asian (EAS) AF: 0.673 AC: 3485 AN: 5176

South Asian (SAS) AF: 0.442 AC: 2130 AN: 4814

European-Finnish (FIN) AF: 0.506 AC: 5347 AN: 10564

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.455 AC: 30917 AN: 67968

Other (OTH) AF: 0.415 AC: 878 AN: 2114

Alfa AF: 0.275 Hom.: 725

Bravo AF: 0.409

Asia WGS AF: 0.556 AC: 1931 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.35
DANN	Benign	0.51
PhyloP100		-0.94
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: rs4953346; hg19: chr2-46558208;