2-46297441-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.213

Publications

13 publications found

Variant links:

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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
autosomal dominant secondary polycythemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EPAS1 links:

ENSG00000304136 (HGNC:):

ENSG00000304136 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
EPAS1	NM_001430.5 link	c.-471C>T		5_prime_UTR_variant	Exon 1 of 16	ENST00000263734.5	NP_001421.2	Q99814B3KW07

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
EPAS1	ENST00000263734.5 link	c.-471C>T	5_prime_UTR_variant	Exon 1 of 16	1	NM_001430.5	ENSP00000263734.3	Q99814
EPAS1	ENST00000449347.5 link	c.-170-301C>T	intron_variant	Intron 1 of 6	3		ENSP00000406137.1	C9J9N2
EPAS1	ENST00000460015.1 link	n.432+3343C>T	intron_variant	Intron 1 of 1	4
ENSG00000304136	ENST00000799986.1 link	n.-190G>A	upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.0207

AC:

3150

AN:

151832

Hom.:

149

Cov.:

show subpopulations

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:

AN:

4850

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

AN XY:

2646

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.0326

AC:

AN:

430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.0612

AC:

AN:

South Asian (SAS)

AF:

0.00377

AC:

AN:

796

European-Finnish (FIN)

AF:

0.0741

AC:

AN:

108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00845

AC:

AN:

3078

Other (OTH)

AF:

0.0320

AC:

AN:

250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0207

AC:

3150

AN:

151950

Hom.:

148

Cov.:

AF XY:

0.0258

AC XY:

1916

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00267

AC:

111

AN:

41512

American (AMR)

AF:

0.0433

AC:

661

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0162

AC:

AN:

3464

East Asian (EAS)

AF:

0.182

AC:

935

AN:

5134

South Asian (SAS)

AF:

0.0104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0793

AC:

833

AN:

10506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00688

AC:

467

AN:

67916

Other (OTH)

AF:

0.0176

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

144

287

431

574

718

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00871

Hom.:

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

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 15, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Erythrocytosis, familial, 4

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.83

PhyloP100

-0.21

PromoterAI

0.054

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over