Genetic Variant EPAS1:c.218-9_218-8insA (chr2-46356142-C-CA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001430.5(EPAS1):c.218-9_218-8insA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000579 in 1,375,738 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 23)

Exomes 𝑓: 0.00065 ( 0 hom. )

Consequence

EPAS1
NM_001430.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.628

Publications

5 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 links:

LINC01820 (HGNC:52625): (long intergenic non-protein coding RNA 1820)

LINC01820 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.218-9_218-8insA		splice_region intron	N/A	NP_001421.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EPAS1	ENST00000263734.5	TSL:1 MANE Select	c.218-9_218-8insA	splice_region intron	N/A	ENSP00000263734.3	Q99814
EPAS1	ENST00000861819.1		c.218-9_218-8insA	splice_region intron	N/A	ENSP00000531878.1
EPAS1	ENST00000861817.1		c.212-9_212-8insA	splice_region intron	N/A	ENSP00000531876.1

Frequencies

GnomAD3 genomes

AF:

0.00000690

AC:

AN:

144960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000230

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000646

AC:

795

AN:

1230660

Hom.:

Cov.:

AF XY:

0.000611

AC XY:

378

AN XY:

618184

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000995

AC:

AN:

32160

American (AMR)

AF:

0.000138

AC:

AN:

43460

Ashkenazi Jewish (ASJ)

AF:

0.000423

AC:

AN:

23630

East Asian (EAS)

AF:

0.000102

AC:

AN:

39074

South Asian (SAS)

AF:

0.000558

AC:

AN:

82382

European-Finnish (FIN)

AF:

0.0000815

AC:

AN:

49070

Middle Eastern (MID)

AF:

0.000630

AC:

AN:

4762

European-Non Finnish (NFE)

AF:

0.000737

AC:

666

AN:

904022

Other (OTH)

AF:

0.000461

AC:

AN:

52100

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.319

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.00000689

AC:

AN:

145078

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

70318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39836

American (AMR)

AF:

0.00

AC:

AN:

14438

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3380

East Asian (EAS)

AF:

0.00

AC:

AN:

5064

South Asian (SAS)

AF:

0.000230

AC:

AN:

4342

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9128

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65702

Other (OTH)

AF:

0.00

AC:

AN:

2012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00

Hom.:

165

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over