2-46325787-A-T

Variant names:

• chr2-46325787-A-T
• rs11125070
• NM_001430.5:c.27-21086A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001430.5(EPAS1):​c.27-21086A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 152,128 control chromosomes in the GnomAD database, including 3,936 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (3936 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 4 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: Genomics England PanelApp, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• autosomal dominant secondary polycythemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.27-21086A>T		intron_variant	Intron 1 of 15	ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.-25A>T		5_prime_UTR_variant	Exon 1 of 16		XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.27-21086A>T		intron_variant	Intron 1 of 15	1	NM_001430.5	ENSP00000263734.3
EPAS1	ENST00000449347.5	c.27-21086A>T		intron_variant	Intron 2 of 6	3		ENSP00000406137.1
EPAS1	ENST00000460015.1	n.433-21086A>T		intron_variant	Intron 1 of 1	4
EPAS1	ENST00000467888.5	n.175-21086A>T		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30928 AN: 152010 Hom.: 3934 Cov.: 32

Gnomad AFR AF: 0.0576

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.194

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.203 AC: 30937 AN: 152128 Hom.: 3936 Cov.: 32 AF XY: 0.208 AC XY: 15483 AN XY: 74338

African (AFR) AF: 0.0575 AC: 2388 AN: 41542

American (AMR) AF: 0.266 AC: 4061 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 597 AN: 3468

East Asian (EAS) AF: 0.254 AC: 1315 AN: 5184

South Asian (SAS) AF: 0.112 AC: 538 AN: 4818

European-Finnish (FIN) AF: 0.363 AC: 3832 AN: 10562

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17666 AN: 67984

Other (OTH) AF: 0.194 AC: 408 AN: 2108

Alfa AF: 0.224 Hom.: 529

Bravo AF: 0.194

Asia WGS AF: 0.200 AC: 697 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.052
DANN	Benign	0.45
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs11125070; hg19: chr2-46552926;