rs4953344

Variant names:

• chr2-46325319-T-C
• rs4953344
• NM_001430.5:c.27-21554T>C

Variant summary

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

The NM_001430.5(EPAS1):​c.27-21554T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 152,236 control chromosomes in the GnomAD database, including 1,807 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 0.14 (1807 hom., cov: 33)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.184
• Publications: 8 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.243 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.27-21554T>C		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.27-21554T>C		intron	N/A	ENSP00000263734.3
	EPAS1	ENST00000449347.5	TSL:3	c.27-21554T>C		intron	N/A	ENSP00000406137.1
	EPAS1	ENST00000460015.1	TSL:4	n.433-21554T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20845 AN: 152118 Hom.: 1804 Cov.: 33

Gnomad AFR AF: 0.0535

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.0295

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.160

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

GnomAD4 genome AF: 0.137 AC: 20855 AN: 152236 Hom.: 1807 Cov.: 33 AF XY: 0.139 AC XY: 10355 AN XY: 74440

African (AFR) AF: 0.0534 AC: 2217 AN: 41548

American (AMR) AF: 0.249 AC: 3809 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 664 AN: 3468

East Asian (EAS) AF: 0.0295 AC: 153 AN: 5182

South Asian (SAS) AF: 0.206 AC: 993 AN: 4818

European-Finnish (FIN) AF: 0.121 AC: 1284 AN: 10602

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11143 AN: 68014

Other (OTH) AF: 0.159 AC: 337 AN: 2114

Alfa AF: 0.160 Hom.: 1628

Bravo AF: 0.140

Asia WGS AF: 0.106 AC: 367 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.8
DANN	Benign	0.36
PhyloP100		0.18
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: rs4953344; hg19: chr2-46552458;