rs5370

Positions:

• chr6-12296022-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001955.5(EDN1):​c.594G>T​(p.Lys198Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,613,552 control chromosomes in the GnomAD database, including 43,252 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3521 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39731 hom.)
• Consequence: EDN1 NM_001955.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0700

Genes affected

EDN1 (HGNC:3176): (endothelin 1) This gene encodes a preproprotein that is proteolytically processed to generate a secreted peptide that belongs to the endothelin/sarafotoxin family. This peptide is a potent vasoconstrictor and its cognate receptors are therapeutic targets in the treatment of pulmonary arterial hypertension. Aberrant expression of this gene may promote tumorigenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002188623).
• BP6: Variant 6-12296022-G-T is Benign according to our data. Variant chr6-12296022-G-T is described in ClinVar as [Benign]. Clinvar id is 16652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDN1	NM_001955.5	c.594G>T	p.Lys198Asn	missense_variant	5/5	ENST00000379375.6	NP_001946.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDN1	ENST00000379375.6	c.594G>T	p.Lys198Asn	missense_variant	5/5	1	NM_001955.5	ENSP00000368683	P1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32244 AN: 151840 Hom.: 3523 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.200

GnomAD3 exomes AF: 0.229 AC: 57654 AN: 251452 Hom.: 7480 AF XY: 0.239 AC XY: 32545 AN XY: 135898

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.211

Gnomad EAS exome AF: 0.281

Gnomad SAS exome AF: 0.402

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.227 AC: 331748 AN: 1461594 Hom.: 39731 Cov.: 33 AF XY: 0.232 AC XY: 168849 AN XY: 727110

Gnomad4 AFR exome AF: 0.188

Gnomad4 AMR exome AF: 0.149

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.283

Gnomad4 SAS exome AF: 0.399

Gnomad4 FIN exome AF: 0.189

Gnomad4 NFE exome AF: 0.218

Gnomad4 OTH exome AF: 0.234

GnomAD4 genome AF: 0.212 AC: 32242 AN: 151958 Hom.: 3521 Cov.: 32 AF XY: 0.214 AC XY: 15904 AN XY: 74260

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.211

Gnomad4 EAS AF: 0.290

Gnomad4 SAS AF: 0.400

Gnomad4 FIN AF: 0.186

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.198

Alfa AF: 0.219 Hom.: 9631

Bravo AF: 0.207

TwinsUK AF: 0.217 AC: 804

ALSPAC AF: 0.219 AC: 845

ESP6500AA AF: 0.196 AC: 865

ESP6500EA AF: 0.211 AC: 1817

ExAC AF: 0.234 AC: 28467

Asia WGS AF: 0.309 AC: 1072 AN: 3478

EpiCase AF: 0.217

EpiControl AF: 0.216

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Auriculocondylar syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

High density lipoprotein cholesterol level quantitative trait locus 7 Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Apr 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.16
Sift	Benign	0.12	T
Sift4G	Uncertain	0.025	D
Polyphen		0.45	P
Vest4		0.037
MutPred		0.078		Loss of methylation at K198 (P = 0.0204);
MPC		0.26
ClinPred		0.0022	T
GERP RS		2.2
Varity_R		0.10
gMVP		0.054

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: rs5370; hg19: chr6-12296255; COSMIC: COSV65080553;