rs141146885

Variant names:

• chr1-21238138-C-T
• rs141146885
• NM_001397.3:c.1385G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-21238138-C-T
• chr1-21238138-C-A

Variant summary

Our verdict is Benign. The variant received -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. 17/22 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
• Publications: 11 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 -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 Benign/Likely_benign. ClinVar VariationId is 258083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 22 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001397.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECE1	NM_001397.3	MANE Select	c.1385G>A	p.Ser462Asn	missense	Exon 11 of 19	NP_001388.1	P42892-1
	ECE1	NM_001113349.2		c.1376G>A	p.Ser459Asn	missense	Exon 10 of 18	NP_001106820.1	P42892-4
	ECE1	NM_001113347.2		c.1349G>A	p.Ser450Asn	missense	Exon 9 of 17	NP_001106818.1	P42892-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECE1	ENST00000374893.11	TSL:1 MANE Select	c.1385G>A	p.Ser462Asn	missense	Exon 11 of 19	ENSP00000364028.6	P42892-1
	ECE1	ENST00000264205.10	TSL:1	c.1376G>A	p.Ser459Asn	missense	Exon 10 of 18	ENSP00000264205.6	P42892-4
	ECE1	ENST00000357071.8	TSL:1	c.1349G>A	p.Ser450Asn	missense	Exon 9 of 17	ENSP00000349581.4	P42892-2

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

GnomAD2 exomes AF: 0.00297 AC: 748 AN: 251432 AF XY: 0.00313

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 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

African (AFR) AF: 0.000836 AC: 28 AN: 33478

American (AMR) AF: 0.00208 AC: 93 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00218 AC: 57 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00187 AC: 161 AN: 86248

European-Finnish (FIN) AF: 0.000655 AC: 35 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.00568 AC: 6315 AN: 1111912

Other (OTH) AF: 0.00374 AC: 226 AN: 60396

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

African (AFR) AF: 0.00106 AC: 44 AN: 41590

American (AMR) AF: 0.00229 AC: 35 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00525 AC: 357 AN: 68032

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00425 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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.055	N
PhyloP100		1.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.082
Sift	Benign	0.38	T
Sift4G	Benign	0.41	T
Polyphen		0.0	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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

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