rs1076669

chr1-21247362-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. 15/21 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin 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, single submitter B:1
• Conservation: PhyloP100: 2.29

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
ECE1	NM_001397.3	c.1022C>T	p.Thr341Ile	missense_variant, splice_region_variant	9/19	ENST00000374893.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECE1	ENST00000374893.11	c.1022C>T	p.Thr341Ile	missense_variant, splice_region_variant	9/19	1	NM_001397.3

Frequencies

GnomAD3 genomes AF: 0.0512 AC: 7793 AN: 152178 Hom.: 269 Cov.: 32

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

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.: 33 AF XY: 0.0719 AC XY: 52308 AN XY: 727234

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.: 32 AF XY: 0.0506 AC XY: 3769 AN XY: 74472

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: 66

ESP6500EA AF: 0.0755 AC: 649

ExAC AF: 0.0555 AC: 6734

Asia WGS AF: 0.0180 AC: 62 AN: 3478

EpiCase AF: 0.0708

EpiControl AF: 0.0705

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.20	N
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	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.38	T
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	T
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

Other links and lift over

dbSNP: rs1076669; hg19: chr1-21573855;