Genetic Variant NM_001397.3:c.1641T>C (chr1-21233587-A-G) – ACMG Classification: Benign (-20 pts)

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.1641T>C(p.Asp547Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.0545 in 1,613,554 control chromosomes in the GnomAD database, including 7,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 3183 hom., cov: 32)

Exomes 𝑓: 0.046 ( 3819 hom. )

Consequence

ECE1
NM_001397.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.01

Publications

5 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 (BayesDel_noAF=-0.49).

BP6

Variant 1-21233587-A-G is Benign according to our data. Variant chr1-21233587-A-G is described in ClinVar as Benign. ClinVar VariationId is 258085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECE1	NM_001397.3 link	c.1641T>C	p.Asp547Asp	synonymous_variant	Exon 14 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.1641T>C	p.Asp547Asp	synonymous_variant	Exon 14 of 19	1	NM_001397.3	ENSP00000364028.6		P42892-1

Frequencies

GnomAD3 genomes

AF:

0.136

AC:

20682

AN:

151976

Hom.:

3171

Cov.:

show subpopulations

Gnomad AFR

AF:

0.381

Gnomad AMI

AF:

0.0308

Gnomad AMR

AF:

0.0701

Gnomad ASJ

AF:

0.0447

Gnomad EAS

AF:

0.00444

Gnomad SAS

AF:

0.0271

Gnomad FIN

AF:

0.0662

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0376

Gnomad OTH

AF:

0.113

GnomAD2 exomes

AF:

0.0589

AC:

14805

AN:

251410

AF XY:

0.0519

show subpopulations

Gnomad AFR exome

AF:

0.386

Gnomad AMR exome

AF:

0.0362

Gnomad ASJ exome

AF:

0.0392

Gnomad EAS exome

AF:

0.00310

Gnomad FIN exome

AF:

0.0664

Gnomad NFE exome

AF:

0.0387

Gnomad OTH exome

AF:

0.0479

GnomAD4 exome

AF:

0.0460

AC:

67243

AN:

1461460

Hom.:

3819

Cov.:

AF XY:

0.0443

AC XY:

32228

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.390

AC:

13050

AN:

33462

American (AMR)

AF:

0.0396

AC:

1769

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0406

AC:

1061

AN:

26136

East Asian (EAS)

AF:

0.00169

AC:

AN:

39696

South Asian (SAS)

AF:

0.0234

AC:

2014

AN:

86244

European-Finnish (FIN)

AF:

0.0625

AC:

3338

AN:

53410

Middle Eastern (MID)

AF:

0.0668

AC:

370

AN:

5536

European-Non Finnish (NFE)

AF:

0.0376

AC:

41832

AN:

1111904

Other (OTH)

AF:

0.0620

AC:

3742

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

3120

6241

9361

12482

15602

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1704

3408

5112

6816

8520

<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:

0.136

AC:

20742

AN:

152094

Hom.:

3183

Cov.:

AF XY:

0.134

AC XY:

9950

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.381

AC:

15814

AN:

41454

American (AMR)

AF:

0.0700

AC:

1069

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0447

AC:

155

AN:

3468

East Asian (EAS)

AF:

0.00426

AC:

AN:

5166

South Asian (SAS)

AF:

0.0272

AC:

131

AN:

4822

European-Finnish (FIN)

AF:

0.0662

AC:

701

AN:

10596

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0376

AC:

2556

AN:

67996

Other (OTH)

AF:

0.117

AC:

246

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

746

1491

2237

2982

3728

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

368

552

736

920

<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:

0.0715

Hom.:

1397

Bravo

AF:

0.148

Asia WGS

AF:

0.0510

AC:

177

AN:

3478

EpiCase

AF:

0.0382

EpiControl

AF:

0.0378

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 12, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

8.4

(source)

DANN

Benign

0.59

PhyloP100

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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