Variant 1-21233567-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_001397.3(ECE1):c.1661A>G(p.Asn554Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000477 in 1,613,452 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056873977).

BS2

High AC in GnomAd4 at 41 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.1661A>G	p.Asn554Ser	missense_variant	14/19	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.1661A>G	p.Asn554Ser	missense_variant	14/19	1	NM_001397.3	ENSP00000364028.6		P42892-1

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000835

AC:

AN:

251414

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461216

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726892

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000269

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000400

Hom.:

Bravo

AF:

0.000370

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

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

Jun 03, 2024

The c.1661A>G (p.N554S) alteration is located in exon 14 (coding exon 14) of the ECE1 gene. This alteration results from a A to G substitution at nucleotide position 1661, causing the asparagine (N) at amino acid position 554 to be replaced by a serine (S). 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

Benign

0.071

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

.;.;.;D;T;.

Eigen

Benign

-0.081

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.86

D;D;D;D;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.057

T;T;T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

2.0

.;.;.;M;.;.

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.7

D;.;D;D;D;D

REVEL

Uncertain

0.36

Sift

Benign

0.41

T;.;T;T;T;T

Sift4G

Benign

0.22

T;.;T;T;T;T

Polyphen

0.072, 0.0040, 0.017, 0.015

.;.;B;B;B;B

Vest4

0.27

MVP

0.87

MPC

0.46

ClinPred

0.040

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.31

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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