rs4953342

Positions:

• chr2-46324908-A-G

Variant summary

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

The NM_001430.5(EPAS1):​c.27-21965A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 152,226 control chromosomes in the GnomAD database, including 5,866 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 0.25 (5866 hom., cov: 34)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.533

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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPAS1	NM_001430.5	c.27-21965A>G		intron_variant		ENST00000263734.5
EPAS1	XM_011532698.3	c.-904A>G		5_prime_UTR_variant	1/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPAS1	ENST00000263734.5	c.27-21965A>G		intron_variant		1	NM_001430.5	P1
EPAS1	ENST00000449347.5	c.27-21965A>G		intron_variant		3
EPAS1	ENST00000460015.1	n.433-21965A>G		intron_variant, non_coding_transcript_variant		4
EPAS1	ENST00000467888.5	n.175-21965A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38298 AN: 152108 Hom.: 5862 Cov.: 34

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.240

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

GnomAD4 genome AF: 0.252 AC: 38311 AN: 152226 Hom.: 5866 Cov.: 34 AF XY: 0.258 AC XY: 19207 AN XY: 74434

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.648

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.383

Gnomad4 NFE AF: 0.280

Gnomad4 OTH AF: 0.245

Alfa AF: 0.271 Hom.: 7625

Bravo AF: 0.247

Asia WGS AF: 0.444 AC: 1542 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.4
DANN	Benign	0.81

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: rs4953342; hg19: chr2-46552047;