chr2-46297772-G-A

Variant names:

• chr2-46297772-G-A
• rs147597862
• NM_001430.5:c.-140G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001430.5(EPAS1):​c.-140G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,186,674 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (10 hom., cov: 32)
  • Exomes 𝑓: 0.011 (87 hom.)
• Consequence: EPAS1 NM_001430.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.21
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, Genomics England PanelApp
• autosomal dominant secondary polycythemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 2-46297772-G-A is Benign according to our data. Variant chr2-46297772-G-A is described in ClinVar as Benign. ClinVar VariationId is 336227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0106 (10966/1034606) while in subpopulation MID AF = 0.0205 (70/3412). AF 95% confidence interval is 0.0167. There are 87 homozygotes in GnomAdExome4. There are 5533 alleles in the male GnomAdExome4 subpopulation. Median coverage is 13. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1367 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.-140G>A		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.-140G>A		5_prime_UTR	Exon 1 of 16	ENSP00000263734.3	Q99814
	EPAS1	ENST00000861819.1		c.-140G>A		5_prime_UTR	Exon 1 of 16	ENSP00000531878.1
	EPAS1	ENST00000861817.1		c.-140G>A		5_prime_UTR	Exon 1 of 16	ENSP00000531876.1

Frequencies

GnomAD3 genomes AF: 0.00900 AC: 1367 AN: 151954 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00399

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.00778

Gnomad SAS AF: 0.00974

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0161

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.0106 AC: 10966 AN: 1034606 Hom.: 87 Cov.: 13 AF XY: 0.0106 AC XY: 5533 AN XY: 523672

African (AFR) AF: 0.00331 AC: 78 AN: 23550

American (AMR) AF: 0.00671 AC: 218 AN: 32482

Ashkenazi Jewish (ASJ) AF: 0.0209 AC: 449 AN: 21490

East Asian (EAS) AF: 0.00264 AC: 88 AN: 33294

South Asian (SAS) AF: 0.00998 AC: 700 AN: 70114

European-Finnish (FIN) AF: 0.00164 AC: 71 AN: 43254

Middle Eastern (MID) AF: 0.0205 AC: 70 AN: 3412

European-Non Finnish (NFE) AF: 0.0114 AC: 8704 AN: 761550

Other (OTH) AF: 0.0129 AC: 588 AN: 45460

GnomAD4 genome AF: 0.00899 AC: 1367 AN: 152068 Hom.: 10 Cov.: 32 AF XY: 0.00837 AC XY: 622 AN XY: 74344

African (AFR) AF: 0.00398 AC: 165 AN: 41502

American (AMR) AF: 0.0129 AC: 197 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 71 AN: 3468

East Asian (EAS) AF: 0.00780 AC: 40 AN: 5128

South Asian (SAS) AF: 0.00975 AC: 47 AN: 4820

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10598

Middle Eastern (MID) AF: 0.0174 AC: 5 AN: 288

European-Non Finnish (NFE) AF: 0.0116 AC: 787 AN: 67954

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.00847 Hom.: 1

Bravo AF: 0.00965

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Erythrocytosis, familial, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.97
PhyloP100		2.2
PromoterAI		-0.098	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=299/1	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: rs147597862; hg19: chr2-46524911;