1-21227230-G-T

Variant names:

• chr1-21227230-G-T
• rs3026903
• NM_001397.3:c.1782-4C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001397.3(ECE1):​c.1782-4C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 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, intron
• Scores: Splicing: ADA: 0.003547
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.370
• Publications: 7 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 -18 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 VariationId is 258087.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 = 0.0275 (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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 86 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECE1	NM_001397.3	MANE Select	c.1782-4C>A		splice_region intron	N/A	NP_001388.1
	ECE1	NM_001113349.2		c.1773-4C>A		splice_region intron	N/A	NP_001106820.1
	ECE1	NM_001113347.2		c.1746-4C>A		splice_region intron	N/A	NP_001106818.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECE1	ENST00000374893.11	TSL:1 MANE Select	c.1782-4C>A		splice_region intron	N/A	ENSP00000364028.6
	ECE1	ENST00000264205.10	TSL:1	c.1773-4C>A		splice_region intron	N/A	ENSP00000264205.6
	ECE1	ENST00000357071.8	TSL:1	c.1746-4C>A		splice_region intron	N/A	ENSP00000349581.4

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

GnomAD2 exomes AF: 0.0281 AC: 7068 AN: 251478 AF XY: 0.0282

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 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

African (AFR) AF: 0.0104 AC: 349 AN: 33476

American (AMR) AF: 0.0136 AC: 609 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0378 AC: 987 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0135 AC: 1165 AN: 86242

European-Finnish (FIN) AF: 0.0631 AC: 3369 AN: 53392

Middle Eastern (MID) AF: 0.0304 AC: 175 AN: 5766

European-Non Finnish (NFE) AF: 0.0357 AC: 39697 AN: 1111480

Other (OTH) AF: 0.0315 AC: 1899 AN: 60370

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

African (AFR) AF: 0.0121 AC: 502 AN: 41568

American (AMR) AF: 0.0226 AC: 346 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 148 AN: 3470

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

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4834

European-Finnish (FIN) AF: 0.0660 AC: 701 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0343 AC: 2334 AN: 68026

Other (OTH) AF: 0.0265 AC: 56 AN: 2114

Alfa AF: 0.0307 Hom.: 39

Bravo AF: 0.0242

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0338

EpiControl AF: 0.0342

ClinVar

ClinVar submissions as Germline

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	-0.36
CADD	Benign	9.9
DANN	Benign	0.73
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3026903; hg19: chr1-21553723;