rs4953354

Variant names:

• chr2-46348249-A-G
• rs4953354
• NM_001430.5:c.217+1186A>G

Variant summary

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

The NM_001430.5(EPAS1):​c.217+1186A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,124 control chromosomes in the GnomAD database, including 3,966 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 0.22 (3966 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.162
• Publications: 31 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]

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPAS1	NM_001430.5	c.217+1186A>G		intron_variant	Intron 2 of 15	ENST00000263734.5	NP_001421.2
EPAS1	XM_011532698.3	c.256+1186A>G		intron_variant	Intron 2 of 15		XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPAS1	ENST00000263734.5	c.217+1186A>G		intron_variant	Intron 2 of 15	1	NM_001430.5	ENSP00000263734.3
EPAS1	ENST00000449347.5	c.217+1186A>G		intron_variant	Intron 3 of 6	3		ENSP00000406137.1
EPAS1	ENST00000475822.1	n.408+1186A>G		intron_variant	Intron 2 of 2	4
LINC01820	ENST00000843948.1	n.103-190T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33487 AN: 152006 Hom.: 3965 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.243

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

GnomAD4 genome AF: 0.220 AC: 33512 AN: 152124 Hom.: 3966 Cov.: 32 AF XY: 0.221 AC XY: 16423 AN XY: 74356

African (AFR) AF: 0.232 AC: 9625 AN: 41486

American (AMR) AF: 0.287 AC: 4379 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 1227 AN: 3470

East Asian (EAS) AF: 0.114 AC: 587 AN: 5170

South Asian (SAS) AF: 0.294 AC: 1418 AN: 4820

European-Finnish (FIN) AF: 0.171 AC: 1809 AN: 10586

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13719 AN: 67996

Other (OTH) AF: 0.240 AC: 505 AN: 2108

Alfa AF: 0.226 Hom.: 1560

Bravo AF: 0.230

Asia WGS AF: 0.196 AC: 684 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.75
DANN	Benign	0.49
PhyloP100		0.16
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: rs4953354; hg19: chr2-46575388;