6-12293945-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001955.5(EDN1):c.238G>A(p.Val80Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000505 in 1,614,124 control chromosomes in the GnomAD database, including 1 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: EDN1 NM_001955.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.757

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005996436).
• BP6: Variant 6-12293945-G-A is Benign according to our data. Variant chr6-12293945-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 757570.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDN1	NM_001955.5	c.238G>A	p.Val80Ile	missense_variant	3/5	ENST00000379375.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDN1	ENST00000379375.6	c.238G>A	p.Val80Ile	missense_variant	3/5	1	NM_001955.5	P1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000713 AC: 179 AN: 251202 Hom.: 1 AF XY: 0.000618 AC XY: 84 AN XY: 135836

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.000731

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000506 AC: 739 AN: 1461848 Hom.: 1 Cov.: 32 AF XY: 0.000479 AC XY: 348 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00412

Gnomad4 NFE exome AF: 0.000425

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74448

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00236

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000574 Hom.: 1

Bravo AF: 0.000215

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000626 AC: 76

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	10
Dann	Benign	0.94
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.18	N
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.14
Sift	Benign	0.44	T
Sift4G	Benign	0.51	T
Polyphen		0.0050	B
Vest4		0.030
MVP		0.75
MPC		0.15
ClinPred		0.012	T
GERP RS		0.83
Varity_R		0.027
gMVP		0.43

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: rs147381256; hg19: chr6-12294178; COSMIC: COSV105828473;