2-46297772-G-A

Variant summary

Our verdict is Benign. Variant got -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:2
• Conservation: PhyloP100: 2.21

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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. gnomad4_exome 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 gnomad4_exome. There are 5533 alleles in male gnomad4_exome subpopulation. Median coverage is 13. This position pass quality control queck.
• BS2: High AC in GnomAd at 1367 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPAS1	NM_001430.5	c.-140G>A		5_prime_UTR_variant	1/16	ENST00000263734.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPAS1	ENST00000263734.5	c.-140G>A		5_prime_UTR_variant	1/16	1	NM_001430.5	P1
EPAS1	ENST00000449347.5	c.-140G>A		5_prime_UTR_variant	2/7	3
EPAS1	ENST00000467888.5	n.9G>A		non_coding_transcript_exon_variant	1/3	5
EPAS1	ENST00000460015.1	n.432+3674G>A		intron_variant, non_coding_transcript_variant		4

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

Gnomad4 AFR exome AF: 0.00331

Gnomad4 AMR exome AF: 0.00671

Gnomad4 ASJ exome AF: 0.0209

Gnomad4 EAS exome AF: 0.00264

Gnomad4 SAS exome AF: 0.00998

Gnomad4 FIN exome AF: 0.00164

Gnomad4 NFE exome AF: 0.0114

Gnomad4 OTH exome AF: 0.0129

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

Gnomad4 AFR AF: 0.00398

Gnomad4 AMR AF: 0.0129

Gnomad4 ASJ AF: 0.0205

Gnomad4 EAS AF: 0.00780

Gnomad4 SAS AF: 0.00975

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00847 Hom.: 1

Bravo AF: 0.00965

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

EPAS1: BS1, BS2 -

Erythrocytosis, familial, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	18
Dann	Benign	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs147597862; hg19: chr2-46524911;