Genetic Variant NM_001397.3:c.1022C>T (chr1-21247362-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -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. 16/22 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 Benign. Variant got -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 id 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

GnomAD3 exomes

AF:

0.0545

AC:

13713

AN:

251460

Hom.:

516

AF XY:

0.0560

AC XY:

7605

AN XY:

135902

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 SAS exome

AF:

0.0399

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

Gnomad4 AFR exome

AF:

0.0101

Gnomad4 AMR exome

AF:

0.0261

Gnomad4 ASJ exome

AF:

0.0488

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0414

Gnomad4 FIN exome

AF:

0.0796

Gnomad4 NFE exome

AF:

0.0828

Gnomad4 OTH exome

AF:

0.0657

GnomAD4 genome

AF:

0.0511

AC:

7787

AN:

152296

Hom.:

269

Cov.:

AF XY:

0.0506

AC XY:

3769

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0144

Gnomad4 AMR

AF:

0.0384

Gnomad4 ASJ

AF:

0.0524

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0390

Gnomad4 FIN

AF:

0.0800

Gnomad4 NFE

AF:

0.0771

Gnomad4 OTH

AF:

0.0445

Alfa

AF:

0.0674

Hom.:

897

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

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;.;.

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

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

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