chr1-21227959-C-G

Position:

• chr1-21227959-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001397.3(ECE1):​c.1753G>C​(p.Ala585Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ECE1 NM_001397.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ECE1	NM_001397.3	c.1753G>C	p.Ala585Pro	missense_variant	15/19	ENST00000374893.11	NP_001388.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ECE1	ENST00000374893.11	c.1753G>C	p.Ala585Pro	missense_variant	15/19	1	NM_001397.3	ENSP00000364028

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.1753G>C (p.A585P) alteration is located in exon 15 (coding exon 15) of the ECE1 gene. This alteration results from a G to C substitution at nucleotide position 1753, causing the alanine (A) at amino acid position 585 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;.;.;T;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.047
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.64	D;D;D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	-0.46	.;.;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.30	N;.;N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.33	T;.;T;T;T;T
Sift4G	Benign	0.59	T;.;T;T;T;T
Polyphen		0.16, 0.0020, 0.0040, 0.30	.;.;B;B;B;B
Vest4		0.30
MutPred		0.74		.;.;.;Gain of catalytic residue at A585 (P = 0.0558);Gain of catalytic residue at A585 (P = 0.0558);.;
MVP		0.85
MPC		1.7
ClinPred		0.87	D
GERP RS		5.0
Varity_R		0.56
gMVP		0.80

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-21554452;