chr1-21227971-C-T

Variant names:

• chr1-21227971-C-T
• rs752979342
• NM_001397.3:c.1741G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001397.3(ECE1):​c.1741G>A​(p.Gly581Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,407,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ECE1 NM_001397.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74
• Publications: 1 publications found

Genes affected

ECE1 (HGNC:3146): (endothelin converting enzyme 1) The protein encoded by this gene is involved in proteolytic processing of endothelin precursors to biologically active peptides. Mutations in this gene are associated with Hirschsprung disease, cardiac defects and autonomic dysfunction. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Sep 2009]

ECE1 Gene-Disease associations (from GenCC):

• essential hypertension, genetic

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001397.3. 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
	ECE1	NM_001397.3	MANE Select	c.1741G>A	p.Gly581Arg	missense	Exon 15 of 19	NP_001388.1	P42892-1
	ECE1	NM_001113349.2		c.1732G>A	p.Gly578Arg	missense	Exon 14 of 18	NP_001106820.1	P42892-4
	ECE1	NM_001113347.2		c.1705G>A	p.Gly569Arg	missense	Exon 13 of 17	NP_001106818.1	P42892-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECE1	ENST00000374893.11	TSL:1 MANE Select	c.1741G>A	p.Gly581Arg	missense	Exon 15 of 19	ENSP00000364028.6	P42892-1
	ECE1	ENST00000264205.10	TSL:1	c.1732G>A	p.Gly578Arg	missense	Exon 14 of 18	ENSP00000264205.6	P42892-4
	ECE1	ENST00000357071.8	TSL:1	c.1705G>A	p.Gly569Arg	missense	Exon 13 of 17	ENSP00000349581.4	P42892-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000587 AC: 1 AN: 170382 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000380

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1407654 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 695040

African (AFR) AF: 0.00 AC: 0 AN: 32136

American (AMR) AF: 0.00 AC: 0 AN: 37184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25290

East Asian (EAS) AF: 0.00 AC: 0 AN: 36622

South Asian (SAS) AF: 0.00 AC: 0 AN: 79920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082676

Other (OTH) AF: 0.00 AC: 0 AN: 58314

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000172 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.90		Gain of methylation at G581 (P = 0.1201)
MVP		0.88
MPC		1.7
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.98
Mutation Taster		=29/71	disease causing

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: rs752979342; hg19: chr1-21554464; COSMIC: COSV51664096;