1-21225121-G-T

Variant names:

• chr1-21225121-G-T
• rs3026905
• NM_001397.3:c.2040+129C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001397.3(ECE1):​c.2040+129C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000179 in 1,114,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: ECE1 NM_001397.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.59
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECE1	NM_001397.3	c.2040+129C>A		intron_variant	Intron 17 of 18	ENST00000374893.11	NP_001388.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECE1	ENST00000374893.11	c.2040+129C>A		intron_variant	Intron 17 of 18	1	NM_001397.3	ENSP00000364028.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000179 AC: 2 AN: 1114382 Hom.: 0 AF XY: 0.00000180 AC XY: 1 AN XY: 555238

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26494

American (AMR) AF: 0.00 AC: 0 AN: 32776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19534

East Asian (EAS) AF: 0.00 AC: 0 AN: 36750

South Asian (SAS) AF: 0.00 AC: 0 AN: 67676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3338

European-Non Finnish (NFE) AF: 0.00000237 AC: 2 AN: 844176

Other (OTH) AF: 0.00 AC: 0 AN: 48444

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.052
DANN	Benign	0.59
PhyloP100		-1.6

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: rs3026905; hg19: chr1-21551614;