chr2-46297555-G-T

Variant names:

• chr2-46297555-G-T
• rs1028727219
• NM_001430.5:c.-357G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001430.5(EPAS1):​c.-357G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000581 in 172,040 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: EPAS1 NM_001430.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.12
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, Genomics England PanelApp
• autosomal dominant secondary polycythemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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.-357G>T		5_prime_UTR	Exon 1 of 16	NP_001421.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	ENST00000263734.5	TSL:1 MANE Select	c.-357G>T		5_prime_UTR	Exon 1 of 16	ENSP00000263734.3	Q99814
	EPAS1	ENST00000861819.1		c.-357G>T		5_prime_UTR	Exon 1 of 16	ENSP00000531878.1
	EPAS1	ENST00000861817.1		c.-357G>T		5_prime_UTR	Exon 1 of 16	ENSP00000531876.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000581 AC: 1 AN: 172040 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 95248

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

African (AFR) AF: 0.00 AC: 0 AN: 1830

American (AMR) AF: 0.00 AC: 0 AN: 6994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3640

East Asian (EAS) AF: 0.00 AC: 0 AN: 5862

South Asian (SAS) AF: 0.00 AC: 0 AN: 33042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 626

European-Non Finnish (NFE) AF: 0.00000978 AC: 1 AN: 102210

Other (OTH) AF: 0.00 AC: 0 AN: 8652

⚠️ 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.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.6
DANN	Benign	0.74
PhyloP100		-2.1
PromoterAI		-0.049	Neutral

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: rs1028727219; hg19: chr2-46524694;