19-11377949-C-T

Variant names:

• chr19-11377949-C-T
• rs200997864
• NM_000121.4:c.*35G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000121.4(EPOR):​c.*35G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000909 in 1,613,106 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00069 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (20 hom.)
• Consequence: EPOR NM_000121.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.555
• Publications: 0 publications found

Genes affected

EPOR (HGNC:3416): (erythropoietin receptor) This gene encodes the erythropoietin receptor which is a member of the cytokine receptor family. Upon erythropoietin binding, this receptor activates Jak2 tyrosine kinase which activates different intracellular pathways including: Ras/MAP kinase, phosphatidylinositol 3-kinase and STAT transcription factors. The stimulated erythropoietin receptor appears to have a role in erythroid cell survival. Defects in the erythropoietin receptor may produce erythroleukemia and familial erythrocytosis. Dysregulation of this gene may affect the growth of certain tumors. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

EPOR Gene-Disease associations (from GenCC):

• primary familial polycythemia due to EPO receptor mutation

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-11377949-C-T is Benign according to our data. Variant chr19-11377949-C-T is described in ClinVar as Benign. ClinVar VariationId is 328137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 105 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000121.4. 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
	EPOR	NM_000121.4	MANE Select	c.*35G>A		3_prime_UTR	Exon 8 of 8	NP_000112.1	P19235-1
	EPOR	NR_033663.2		n.1919G>A		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPOR	ENST00000222139.11	TSL:1 MANE Select	c.*35G>A		3_prime_UTR	Exon 8 of 8	ENSP00000222139.5	P19235-1
	EPOR	ENST00000586890.5	TSL:1	n.*1305G>A		non_coding_transcript_exon	Exon 9 of 9	ENSP00000467230.1	K7EP50
	EPOR	ENST00000588681.5	TSL:1	n.1947G>A		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes AF: 0.000683 AC: 104 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00165 AC: 411 AN: 248558 AF XY: 0.00227

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000454

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.000932 AC: 1361 AN: 1460786 Hom.: 20 Cov.: 31 AF XY: 0.00125 AC XY: 909 AN XY: 726648

African (AFR) AF: 0.0000598 AC: 2 AN: 33460

American (AMR) AF: 0.000805 AC: 36 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00970 AC: 836 AN: 86206

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53012

Middle Eastern (MID) AF: 0.00353 AC: 19 AN: 5390

European-Non Finnish (NFE) AF: 0.000333 AC: 370 AN: 1111830

Other (OTH) AF: 0.000812 AC: 49 AN: 60336

GnomAD4 genome AF: 0.000689 AC: 105 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00196 AC: 30 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00621 AC: 30 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000753 Hom.: 0

Bravo AF: 0.000706

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Primary familial polycythemia due to EPO receptor mutation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.8
DANN	Benign	0.65
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism

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: rs200997864; hg19: chr19-11488625;