rs6413478

chr6-12295984-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001955.5(EDN1):c.556G>A(p.Val186Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000734 in 1,614,002 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00048 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (1 hom.)
• Consequence: EDN1 NM_001955.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021871656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDN1	NM_001955.5	c.556G>A	p.Val186Ile	missense_variant	5/5	ENST00000379375.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDN1	ENST00000379375.6	c.556G>A	p.Val186Ile	missense_variant	5/5	1	NM_001955.5	P1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152096 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000453 AC: 114 AN: 251468 Hom.: 0 AF XY: 0.000434 AC XY: 59 AN XY: 135902

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000809

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000760 AC: 1111 AN: 1461788 Hom.: 1 Cov.: 30 AF XY: 0.000710 AC XY: 516 AN XY: 727208

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000921

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152214 Hom.: 1 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74420

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000765

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000651 Hom.: 0

Bravo AF: 0.000484

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000527 AC: 64

EpiCase AF: 0.000600

EpiControl AF: 0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with EDN1-related conditions. This variant is present in population databases (rs6413478, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 186 of the EDN1 protein (p.Val186Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	5.1
Dann	Benign	0.36
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.92	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0050	B
Vest4		0.047
MVP		0.61
MPC		0.15
ClinPred		0.0012	T
GERP RS		2.4
Varity_R		0.021
gMVP		0.058

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: rs6413478; hg19: chr6-12296217;