rs1076669

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001397.3(ECE1):c.1022C>T(p.Thr341Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0711 in 1,614,150 control chromosomes in the GnomAD database, including 4,602 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.051 ( 269 hom., cov: 32)

Exomes 𝑓: 0.073 ( 4333 hom. )

Consequence

ECE1
NM_001397.3 missense, splice_region

Scores

Splicing: ADA: 0.005379

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.29

Publications

32 publications found

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 Gene-Disease associations (from GenCC):

essential hypertension, genetic
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ECE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018210113).

BP6

Variant 1-21247362-G-A is Benign according to our data. Variant chr1-21247362-G-A is described in ClinVar as Benign. ClinVar VariationId is 258079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECE1	NM_001397.3 link	c.1022C>T	p.Thr341Ile	missense_variant, splice_region_variant	Exon 9 of 19	ENST00000374893.11	NP_001388.1	P42892-1A1PUP8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECE1	ENST00000374893.11 link	c.1022C>T	p.Thr341Ile	missense_variant, splice_region_variant	Exon 9 of 19	1	NM_001397.3	ENSP00000364028.6		P42892-1

Frequencies

GnomAD3 genomes

AF:

0.0512

AC:

7793

AN:

152178

Hom.:

269

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0144

Gnomad AMI

AF:

0.0319

Gnomad AMR

AF:

0.0386

Gnomad ASJ

AF:

0.0524

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0387

Gnomad FIN

AF:

0.0800

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0771

Gnomad OTH

AF:

0.0450

GnomAD2 exomes

AF:

0.0545

AC:

13713

AN:

251460

AF XY:

0.0560

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.0244

Gnomad ASJ exome

AF:

0.0452

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0810

Gnomad NFE exome

AF:

0.0784

Gnomad OTH exome

AF:

0.0497

GnomAD4 exome

AF:

0.0732

AC:

106942

AN:

1461854

Hom.:

4333

Cov.:

AF XY:

0.0719

AC XY:

52308

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0101

AC:

339

AN:

33480

American (AMR)

AF:

0.0261

AC:

1167

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0488

AC:

1275

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0414

AC:

3570

AN:

86254

European-Finnish (FIN)

AF:

0.0796

AC:

4254

AN:

53420

Middle Eastern (MID)

AF:

0.0511

AC:

295

AN:

5768

European-Non Finnish (NFE)

AF:

0.0828

AC:

92070

AN:

1111986

Other (OTH)

AF:

0.0657

AC:

3969

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

5847

11694

17542

23389

29236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3396

6792

10188

13584

16980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0511

AC:

7787

AN:

152296

Hom.:

269

Cov.:

AF XY:

0.0506

AC XY:

3769

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0144

AC:

598

AN:

41576

American (AMR)

AF:

0.0384

AC:

588

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0524

AC:

182

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.0390

AC:

188

AN:

4826

European-Finnish (FIN)

AF:

0.0800

AC:

848

AN:

10602

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0771

AC:

5244

AN:

68016

Other (OTH)

AF:

0.0445

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

376

751

1127

1502

1878

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0646

Hom.:

1191

Bravo

AF:

0.0469

TwinsUK

AF:

0.0866

AC:

321

ALSPAC

AF:

0.0908

AC:

350

ESP6500AA

AF:

0.0150

AC:

ESP6500EA

AF:

0.0755

AC:

649

ExAC

AF:

0.0555

AC:

6734

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.0708

EpiControl

AF:

0.0705

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

.;.;.;D;T;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.79

T;T;T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;.;.;L;.;.

PhyloP100

2.3

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.0

N;.;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.17

T;.;T;T;T;T

Sift4G

Benign

0.17

T;.;T;T;T;T

Polyphen

0.013, 0.0070, 0.040, 0.0090

.;.;B;B;B;B

Vest4

0.18

MPC

0.70

ClinPred

0.0098

GERP RS

4.6

Varity_R

0.066

gMVP

0.32

Mutation Taster

=79/21

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0054

dbscSNV1_RF

Benign

0.022

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over