rs4953344

chr2-46325319-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001430.5(EPAS1):c.27-21554T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 152,236 control chromosomes in the GnomAD database, including 1,807 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 0.14 (1807 hom., cov: 33)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.184

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPAS1	NM_001430.5	c.27-21554T>C		intron_variant		ENST00000263734.5
EPAS1	XM_011532698.3	c.-493T>C		5_prime_UTR_variant	1/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPAS1	ENST00000263734.5	c.27-21554T>C		intron_variant		1	NM_001430.5	P1
EPAS1	ENST00000449347.5	c.27-21554T>C		intron_variant		3
EPAS1	ENST00000460015.1	n.433-21554T>C		intron_variant, non_coding_transcript_variant		4
EPAS1	ENST00000467888.5	n.175-21554T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20845 AN: 152118 Hom.: 1804 Cov.: 33

Gnomad AFR AF: 0.0535

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.0295

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.160

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

GnomAD4 genome AF: 0.137 AC: 20855 AN: 152236 Hom.: 1807 Cov.: 33 AF XY: 0.139 AC XY: 10355 AN XY: 74440

Gnomad4 AFR AF: 0.0534

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.0295

Gnomad4 SAS AF: 0.206

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.164

Gnomad4 OTH AF: 0.159

Alfa AF: 0.165 Hom.: 1200

Bravo AF: 0.140

Asia WGS AF: 0.106 AC: 367 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	6.8
Dann	Benign	0.36

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: rs4953344; hg19: chr2-46552458;