6-12294025-A-T

Variant names:

• chr6-12294025-A-T
• rs5369
• NM_001955.5:c.318A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001955.5(EDN1):​c.318A>T​(p.Glu106Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E106E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EDN1 NM_001955.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.442
• Publications: 57 publications found

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]

EDN1 Gene-Disease associations (from GenCC):

• question mark ears, isolated

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• auriculocondylar syndrome 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• auriculocondylar syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000302734 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07423562).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001955.5. 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
	EDN1	NM_001955.5	MANE Select	c.318A>T	p.Glu106Asp	missense	Exon 3 of 5	NP_001946.3
	EDN1	NM_001416563.1		c.318A>T	p.Glu106Asp	missense	Exon 4 of 6	NP_001403492.1	Q6FH53
	EDN1	NM_001416564.1		c.318A>T	p.Glu106Asp	missense	Exon 4 of 6	NP_001403493.1	Q6FH53

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDN1	ENST00000379375.6	TSL:1 MANE Select	c.318A>T	p.Glu106Asp	missense	Exon 3 of 5	ENSP00000368683.5	P05305
	EDN1	ENST00000877370.1		c.342A>T	p.Glu114Asp	missense	Exon 3 of 5	ENSP00000547429.1
	EDN1	ENST00000971811.1		c.342A>T	p.Glu114Asp	missense	Exon 5 of 7	ENSP00000641870.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.6
DANN	Benign	0.70
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.44
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.097
Sift	Benign	0.58	T
Sift4G	Benign	0.62	T
Polyphen		0.020	B
Vest4		0.14
MutPred		0.15		Loss of methylation at K101 (P = 0.1204)
MVP		0.60
MPC		0.17
ClinPred		0.028	T
GERP RS		2.9
Varity_R		0.045
gMVP		0.23
Mutation Taster		=94/6	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: rs5369; hg19: chr6-12294258;