rs3026903

chr1-21227230-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001397.3(ECE1):c.1782-4C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,613,586 control chromosomes in the GnomAD database, including 1,009 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 0.027 (86 hom., cov: 32)
  • Exomes 𝑓: 0.033 (923 hom.)
• Consequence: ECE1 NM_001397.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.003547
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.370

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 1-21227230-G-T is Benign according to our data. Variant chr1-21227230-G-T is described in ClinVar as [Benign]. Clinvar id is 258087.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0275 (4184/152316) while in subpopulation NFE AF= 0.0343 (2334/68026). AF 95% confidence interval is 0.0331. There are 86 homozygotes in gnomad4. There are 2116 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 4184 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECE1	NM_001397.3	c.1782-4C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000374893.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECE1	ENST00000374893.11	c.1782-4C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001397.3

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4184 AN: 152198 Hom.: 86 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0660

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0281 AC: 7068 AN: 251478 Hom.: 130 AF XY: 0.0282 AC XY: 3828 AN XY: 135920

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0361

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0129

Gnomad FIN exome AF: 0.0667

Gnomad NFE exome AF: 0.0358

Gnomad OTH exome AF: 0.0270

GnomAD4 exome AF: 0.0330 AC: 48250 AN: 1461270 Hom.: 923 Cov.: 31 AF XY: 0.0326 AC XY: 23685 AN XY: 726992

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.0378

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0135

Gnomad4 FIN exome AF: 0.0631

Gnomad4 NFE exome AF: 0.0357

Gnomad4 OTH exome AF: 0.0315

GnomAD4 genome AF: 0.0275 AC: 4184 AN: 152316 Hom.: 86 Cov.: 32 AF XY: 0.0284 AC XY: 2116 AN XY: 74480

Gnomad4 AFR AF: 0.0121

Gnomad4 AMR AF: 0.0226

Gnomad4 ASJ AF: 0.0427

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.0660

Gnomad4 NFE AF: 0.0343

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0311 Hom.: 32

Bravo AF: 0.0242

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0338

EpiControl AF: 0.0342

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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
BayesDel_noAF	Benign	-0.36
Cadd	Benign	9.9
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0035
dbscSNV1_RF	Benign	0.040
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: rs3026903; hg19: chr1-21553723;