NM_001430.5:c.-347T>G

Variant names:

• chr2-46297565-T-G
• rs192684713
• NM_001430.5:c.-347T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001430.5(EPAS1):​c.-347T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0005 in 334,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: EPAS1 NM_001430.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.515
• 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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS2: High AC in GnomAd4 at 67 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	NM_001430.5	MANE Select	c.-347T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001421.2
	EPAS1	NM_001430.5	MANE Select	c.-347T>G		5_prime_UTR	Exon 1 of 16	NP_001421.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	ENST00000263734.5	TSL:1 MANE Select	c.-347T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000263734.3	Q99814
	EPAS1	ENST00000263734.5	TSL:1 MANE Select	c.-347T>G		5_prime_UTR	Exon 1 of 16	ENSP00000263734.3	Q99814
	EPAS1	ENST00000861819.1		c.-347T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000531878.1

Frequencies

GnomAD3 genomes AF: 0.000441 AC: 67 AN: 151908 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000549 AC: 100 AN: 182220 Hom.: 0 Cov.: 0 AF XY: 0.000596 AC XY: 60 AN XY: 100614

African (AFR) AF: 0.00 AC: 0 AN: 2156

American (AMR) AF: 0.000551 AC: 4 AN: 7254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4026

East Asian (EAS) AF: 0.00 AC: 0 AN: 6664

South Asian (SAS) AF: 0.000418 AC: 14 AN: 33524

European-Finnish (FIN) AF: 0.000407 AC: 4 AN: 9818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 690

European-Non Finnish (NFE) AF: 0.000689 AC: 75 AN: 108780

Other (OTH) AF: 0.000322 AC: 3 AN: 9308

GnomAD4 genome AF: 0.000441 AC: 67 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 31 AN XY: 74322

African (AFR) AF: 0.000290 AC: 12 AN: 41416

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 67964

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000486 Hom.: 0

Bravo AF: 0.000480

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Erythrocytosis, familial, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	14
DANN	Benign	0.63
PhyloP100		0.52
PromoterAI		-0.11	Neutral
Mutation Taster		=300/0	polymorphism

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: rs192684713; hg19: chr2-46524704;