rs587777233

Variant names:

• chr6-12292467-T-A
• rs587777233
• NM_001955.5:c.191T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001955.5(EDN1):​c.191T>A​(p.Val64Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EDN1 NM_001955.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.74
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae)
• auriculocondylar syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000302734 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 6-12292467-T-A is Pathogenic according to our data. Variant chr6-12292467-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 120214.Status of the report is no_assertion_criteria_provided, 0 stars.

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.191T>A	p.Val64Asp	missense	Exon 2 of 5	NP_001946.3
	EDN1	NM_001416563.1		c.191T>A	p.Val64Asp	missense	Exon 3 of 6	NP_001403492.1	Q6FH53
	EDN1	NM_001416564.1		c.191T>A	p.Val64Asp	missense	Exon 3 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.191T>A	p.Val64Asp	missense	Exon 2 of 5	ENSP00000368683.5	P05305
	EDN1	ENST00000877370.1		c.191T>A	p.Val64Asp	missense	Exon 2 of 5	ENSP00000547429.1
	EDN1	ENST00000971811.1		c.191T>A	p.Val64Asp	missense	Exon 4 of 7	ENSP00000641870.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Question mark ears, isolated (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.78		Gain of disorder (P = 0.0541)
MVP		0.98
MPC		0.95
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.98
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs587777233; hg19: chr6-12292700;