chr1-21247362-G-A

Variant names:

• chr1-21247362-G-A
• rs1076669
• NM_001397.3:c.1022C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 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

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)

ACMG classification

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	c.1022C>T	p.Thr341Ile	missense_variant, splice_region_variant	Exon 9 of 19	ENST00000374893.11	NP_001388.1

Ensembl

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

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

GnomAD2 exomes AF: 0.0545 AC: 13713 AN: 251460 AF XY: 0.0560

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

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: 3 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

GnomAD4 genome AF: 0.0511 AC: 7787 AN: 152296 Hom.: 269 Cov.: 32 AF XY: 0.0506 AC XY: 3769 AN XY: 74472

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: 2 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: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0771 AC: 5244 AN: 68016

Other (OTH) AF: 0.0445 AC: 94 AN: 2112

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: 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:2

Revision: criteria provided, multiple submitters, no conflicts

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	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	.;.;.;D;T;.
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
MutationAssessor	Benign	1.8	.;.;.;L;.;.
PhyloP100		2.3
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
Mutation Taster		=79/21	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1076669; hg19: chr1-21573855;