chr1-21225387-C-A

Variant names:

• chr1-21225387-C-A
• rs1316358496
• NM_001397.3:c.1903G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001397.3(ECE1):​c.1903G>T​(p.Val635Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V635M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ECE1 NM_001397.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.54

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25542694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECE1	NM_001397.3	c.1903G>T	p.Val635Leu	missense_variant	Exon 17 of 19	ENST00000374893.11	NP_001388.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECE1	ENST00000374893.11	c.1903G>T	p.Val635Leu	missense_variant	Exon 17 of 19	1	NM_001397.3	ENSP00000364028.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.0055	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.40	.;.;.;T;T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;T;T;T;T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.26	T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	-0.34	.;.;.;N;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.92	N;.;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.76	T;.;T;T;T;T
Sift4G	Benign	0.53	T;.;T;T;T;T
Polyphen		0.063, 0.0020, 0.0050, 0.11	.;.;B;B;B;B
Vest4		0.37
MutPred		0.49		.;.;.;Loss of MoRF binding (P = 0.096);Loss of MoRF binding (P = 0.096);.;
MVP		0.58
MPC		1.5
ClinPred		0.88	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.75

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

LitVar

Other links and lift over

dbSNP: rs1316358496; hg19: chr1-21551880;