rs28368004

Variant names:

• chr1-21244982-G-A
• rs28368004
• NM_001397.3:c.1278+7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001397.3(ECE1):​c.1278+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0306 in 1,612,874 control chromosomes in the GnomAD database, including 966 homozygotes. In-silico tool predicts 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 0.024 (84 hom., cov: 32)
  • Exomes 𝑓: 0.031 (882 hom.)
• Consequence: ECE1 NM_001397.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002036
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.26
• Publications: 4 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=-0.78).
• BP6: Variant 1-21244982-G-A is Benign according to our data. Variant chr1-21244982-G-A is described in ClinVar as Benign. ClinVar VariationId is 258082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0238 (3626/152282) while in subpopulation NFE AF = 0.0353 (2401/68016). AF 95% confidence interval is 0.0341. There are 84 homozygotes in GnomAd4. There are 1892 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 84 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.1278+7C>T		splice_region intron	N/A	NP_001388.1	P42892-1
	ECE1	NM_001113349.2		c.1269+7C>T		splice_region intron	N/A	NP_001106820.1	P42892-4
	ECE1	NM_001113347.2		c.1242+7C>T		splice_region intron	N/A	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.1278+7C>T		splice_region intron	N/A	ENSP00000364028.6	P42892-1
	ECE1	ENST00000264205.10	TSL:1	c.1269+7C>T		splice_region intron	N/A	ENSP00000264205.6	P42892-4
	ECE1	ENST00000357071.8	TSL:1	c.1242+7C>T		splice_region intron	N/A	ENSP00000349581.4	P42892-2

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3625 AN: 152164 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.0592

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0353

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0241 AC: 6054 AN: 251418 AF XY: 0.0244

Gnomad AFR exome AF: 0.00615

Gnomad AMR exome AF: 0.00931

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0619

Gnomad NFE exome AF: 0.0328

Gnomad OTH exome AF: 0.0256

GnomAD4 exome AF: 0.0313 AC: 45659 AN: 1460592 Hom.: 882 Cov.: 31 AF XY: 0.0306 AC XY: 22262 AN XY: 726714

African (AFR) AF: 0.00463 AC: 155 AN: 33456

American (AMR) AF: 0.00997 AC: 446 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 408 AN: 26122

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39686

South Asian (SAS) AF: 0.00813 AC: 701 AN: 86240

European-Finnish (FIN) AF: 0.0605 AC: 3229 AN: 53398

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5768

European-Non Finnish (NFE) AF: 0.0351 AC: 39000 AN: 1110850

Other (OTH) AF: 0.0274 AC: 1652 AN: 60354

GnomAD4 genome AF: 0.0238 AC: 3626 AN: 152282 Hom.: 84 Cov.: 32 AF XY: 0.0254 AC XY: 1892 AN XY: 74472

African (AFR) AF: 0.00575 AC: 239 AN: 41546

American (AMR) AF: 0.0131 AC: 201 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00746 AC: 36 AN: 4828

European-Finnish (FIN) AF: 0.0592 AC: 628 AN: 10606

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0353 AC: 2401 AN: 68016

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0296 Hom.: 144

Bravo AF: 0.0195

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0311

EpiControl AF: 0.0303

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.1
DANN	Benign	0.67
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.026
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: rs28368004; hg19: chr1-21571475;