2-46297441-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001430.5(EPAS1):c.-471C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 156,800 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (148 hom., cov: 32)
  • Exomes 𝑓: 0.013 (2 hom.)
• Consequence: EPAS1 NM_001430.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.213

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-46297441-C-T is Benign according to our data. Variant chr2-46297441-C-T is described in ClinVar as [Benign]. Clinvar id is 336219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPAS1	NM_001430.5	c.-471C>T		5_prime_UTR_variant	1/16	ENST00000263734.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPAS1	ENST00000263734.5	c.-471C>T		5_prime_UTR_variant	1/16	1	NM_001430.5	P1
EPAS1	ENST00000449347.5	c.-170-301C>T		intron_variant		3
EPAS1	ENST00000460015.1	n.432+3343C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0207 AC: 3150 AN: 151832 Hom.: 149 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0430

Gnomad ASJ AF: 0.0162

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.0793

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00688

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.0134 AC: 65 AN: 4850 Hom.: 2 Cov.: 0 AF XY: 0.0121 AC XY: 32 AN XY: 2646

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0326

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0612

Gnomad4 SAS exome AF: 0.00377

Gnomad4 FIN exome AF: 0.0741

Gnomad4 NFE exome AF: 0.00845

Gnomad4 OTH exome AF: 0.0320

GnomAD4 genome AF: 0.0207 AC: 3150 AN: 151950 Hom.: 148 Cov.: 32 AF XY: 0.0258 AC XY: 1916 AN XY: 74296

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.0433

Gnomad4 ASJ AF: 0.0162

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0793

Gnomad4 NFE AF: 0.00688

Gnomad4 OTH AF: 0.0176

Alfa AF: 0.00871 Hom.: 1

Bravo AF: 0.0171

Asia WGS AF: 0.0810 AC: 281 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

GeneDx

Jun 15, 2019

This variant is associated with the following publications: (PMID: 20495570) -

Erythrocytosis, familial, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.70
Cadd	Benign	7.9
Dann	Benign	0.83
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: rs17039192; hg19: chr2-46524580;