Variant 1-21227989-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_ModerateBS2_Supporting

The NM_001397.3(ECE1):c.1723G>A(p.Glu575Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,565,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000078 ( 0 hom. )

Consequence

ECE1
NM_001397.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.82

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.865

BS2

High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ECE1	NM_001397.3 link	c.1723G>A	p.Glu575Lys	missense_variant	15/19	ENST00000374893.11	NP_001388.1	P42892-1A1PUP8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ECE1	ENST00000374893.11 link	c.1723G>A	p.Glu575Lys	missense_variant	15/19	1	NM_001397.3	ENSP00000364028.6		P42892-1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000778

AC:

AN:

1413258

Hom.:

Cov.:

AF XY:

0.00000573

AC XY:

AN XY:

698358

show subpopulations

Gnomad4 AFR exome

AF:

0.0000309

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000921

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151952

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000676

Hom.:

ExAC

AF:

0.00000847

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2024

The c.1723G>A (p.E575K) alteration is located in exon 15 (coding exon 15) of the ECE1 gene. This alteration results from a G to A substitution at nucleotide position 1723, causing the glutamic acid (E) at amino acid position 575 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

.;.;.;D;T;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.86

D;D;D;D;D;D

MetaSVM

Pathogenic

0.79

MutationAssessor

Uncertain

2.3

.;.;.;M;.;.

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.7

N;.;N;N;N;N

REVEL

Pathogenic

0.74

Sift

Uncertain

0.012

D;.;D;D;D;D

Sift4G

Benign

0.13

T;.;T;T;T;T

Polyphen

0.99, 0.78, 0.42

.;.;D;P;B;D

Vest4

0.65

MutPred

0.64

.;.;.;Gain of methylation at E575 (P = 0.0163);Gain of methylation at E575 (P = 0.0163);.;

MVP

0.90

MPC

1.6

ClinPred

0.72

GERP RS

5.0

Varity_R

0.75

gMVP

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over