NM_001397.3:c.1641T>C

Variant names:

• chr1-21233587-A-G
• rs2228321
• NM_001397.3:c.1641T>C

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.1641T>C​(p.Asp547Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.0545 in 1,613,554 control chromosomes in the GnomAD database, including 7,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (3183 hom., cov: 32)
  • Exomes 𝑓: 0.046 (3819 hom.)
• Consequence: ECE1 NM_001397.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.01
• Publications: 5 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 (BayesDel_noAF=-0.49).
• BP6: Variant 1-21233587-A-G is Benign according to our data. Variant chr1-21233587-A-G is described in ClinVar as Benign. ClinVar VariationId is 258085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

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.1641T>C	p.Asp547Asp	synonymous	Exon 14 of 19	NP_001388.1	P42892-1
	ECE1	NM_001113349.2		c.1632T>C	p.Asp544Asp	synonymous	Exon 13 of 18	NP_001106820.1	P42892-4
	ECE1	NM_001113347.2		c.1605T>C	p.Asp535Asp	synonymous	Exon 12 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.1641T>C	p.Asp547Asp	synonymous	Exon 14 of 19	ENSP00000364028.6	P42892-1
	ECE1	ENST00000264205.10	TSL:1	c.1632T>C	p.Asp544Asp	synonymous	Exon 13 of 18	ENSP00000264205.6	P42892-4
	ECE1	ENST00000357071.8	TSL:1	c.1605T>C	p.Asp535Asp	synonymous	Exon 12 of 17	ENSP00000349581.4	P42892-2

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20682 AN: 151976 Hom.: 3171 Cov.: 32

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0701

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.00444

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.0662

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0376

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.0589 AC: 14805 AN: 251410 AF XY: 0.0519

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.0362

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.00310

Gnomad FIN exome AF: 0.0664

Gnomad NFE exome AF: 0.0387

Gnomad OTH exome AF: 0.0479

GnomAD4 exome AF: 0.0460 AC: 67243 AN: 1461460 Hom.: 3819 Cov.: 31 AF XY: 0.0443 AC XY: 32228 AN XY: 727030

African (AFR) AF: 0.390 AC: 13050 AN: 33462

American (AMR) AF: 0.0396 AC: 1769 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 1061 AN: 26136

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39696

South Asian (SAS) AF: 0.0234 AC: 2014 AN: 86244

European-Finnish (FIN) AF: 0.0625 AC: 3338 AN: 53410

Middle Eastern (MID) AF: 0.0668 AC: 370 AN: 5536

European-Non Finnish (NFE) AF: 0.0376 AC: 41832 AN: 1111904

Other (OTH) AF: 0.0620 AC: 3742 AN: 60350

GnomAD4 genome AF: 0.136 AC: 20742 AN: 152094 Hom.: 3183 Cov.: 32 AF XY: 0.134 AC XY: 9950 AN XY: 74366

African (AFR) AF: 0.381 AC: 15814 AN: 41454

American (AMR) AF: 0.0700 AC: 1069 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3468

East Asian (EAS) AF: 0.00426 AC: 22 AN: 5166

South Asian (SAS) AF: 0.0272 AC: 131 AN: 4822

European-Finnish (FIN) AF: 0.0662 AC: 701 AN: 10596

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0376 AC: 2556 AN: 67996

Other (OTH) AF: 0.117 AC: 246 AN: 2108

Alfa AF: 0.0715 Hom.: 1397

Bravo AF: 0.148

Asia WGS AF: 0.0510 AC: 177 AN: 3478

EpiCase AF: 0.0382

EpiControl AF: 0.0378

ClinVar

ClinVar submissions

Significance: 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
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.4
DANN	Benign	0.59
PhyloP100		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs2228321; hg19: chr1-21560080;