rs141146885

chr1-21238138-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001397.3(ECE1):c.1385G>A(p.Ser462Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,614,136 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (22 hom.)
• Consequence: ECE1 NM_001397.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.05

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057007372).
• BP6: Variant 1-21238138-C-T is Benign according to our data. Variant chr1-21238138-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21238138-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 510 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECE1	NM_001397.3	c.1385G>A	p.Ser462Asn	missense_variant	11/19	ENST00000374893.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECE1	ENST00000374893.11	c.1385G>A	p.Ser462Asn	missense_variant	11/19	1	NM_001397.3

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 510 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00297 AC: 748 AN: 251432 Hom.: 4 AF XY: 0.00313 AC XY: 426 AN XY: 135892

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00475

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00474 AC: 6929 AN: 1461778 Hom.: 22 Cov.: 31 AF XY: 0.00460 AC XY: 3345 AN XY: 727188

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00187

Gnomad4 FIN exome AF: 0.000655

Gnomad4 NFE exome AF: 0.00568

Gnomad4 OTH exome AF: 0.00374

GnomAD4 genome AF: 0.00335 AC: 510 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.00275 AC XY: 205 AN XY: 74502

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00525

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00445 Hom.: 7

Bravo AF: 0.00328

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00298 AC: 362

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 08, 2017	- -

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	0.056
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	14
Dann	Benign	0.85
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.73	T;T;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0057	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.65	N;.;N;N;N;N
REVEL	Benign	0.082
Sift	Benign	0.38	T;.;T;T;T;T
Sift4G	Benign	0.41	T;.;T;T;T;T
Polyphen		0.0	.;.;B;B;B;B
Vest4		0.085
MVP		0.26
MPC		0.54
ClinPred		0.0020	T
GERP RS		0.51
Varity_R		0.057
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs141146885; hg19: chr1-21564631; COSMIC: COSV105822965; COSMIC: COSV105822965;