ENST00000449347.5:c.-170-469G>A

Variant names:

• chr2-46297273-G-A
• rs188057474
• ENST00000449347.5:c.-170-469G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000449347.5(EPAS1):​c.-170-469G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0732 in 149,064 control chromosomes in the GnomAD database, including 1,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.073 (1197 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPAS1 ENST00000449347.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.274
• Publications: 0 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, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• autosomal dominant secondary polycythemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000304136 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-46297273-G-A is Benign according to our data. Variant chr2-46297273-G-A is described in ClinVar as Benign. ClinVar VariationId is 1232911.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000449347.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	NM_001430.5	MANE Select	c.-639G>A		upstream_gene	N/A	NP_001421.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	ENST00000449347.5	TSL:3	c.-170-469G>A		intron	N/A	ENSP00000406137.1	C9J9N2
	EPAS1	ENST00000460015.1	TSL:4	n.432+3175G>A		intron	N/A
	EPAS1	ENST00000263734.5	TSL:1 MANE Select	c.-639G>A		upstream_gene	N/A	ENSP00000263734.3	Q99814

Frequencies

GnomAD3 genomes AF: 0.0731 AC: 10882 AN: 148958 Hom.: 1189 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0336

Gnomad ASJ AF: 0.00117

Gnomad EAS AF: 0.0101

Gnomad SAS AF: 0.0551

Gnomad FIN AF: 0.000947

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.0555

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0732 AC: 10916 AN: 149064 Hom.: 1197 Cov.: 32 AF XY: 0.0722 AC XY: 5253 AN XY: 72714

African (AFR) AF: 0.237 AC: 9761 AN: 41102

American (AMR) AF: 0.0336 AC: 504 AN: 15000

Ashkenazi Jewish (ASJ) AF: 0.00117 AC: 4 AN: 3418

East Asian (EAS) AF: 0.00997 AC: 51 AN: 5116

South Asian (SAS) AF: 0.0549 AC: 265 AN: 4826

European-Finnish (FIN) AF: 0.000947 AC: 9 AN: 9504

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00307 AC: 205 AN: 66818

Other (OTH) AF: 0.0549 AC: 114 AN: 2076

Alfa AF: 0.00291 Hom.: 3

Bravo AF: 0.0812

Asia WGS AF: 0.0550 AC: 184 AN: 3358

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Benign	0.97
PhyloP100		-0.27
PromoterAI		0.081	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs188057474; hg19: chr2-46524412;