rs532757890
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_004826.4(ECEL1):c.1210C>T(p.Arg404Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
ECEL1
NM_004826.4 missense
NM_004826.4 missense
Scores
9
9
1
Clinical Significance
Conservation
PhyloP100: 8.05
Genes affected
ECEL1 (HGNC:3147): (endothelin converting enzyme like 1) This gene encodes a member of the M13 family of endopeptidases. Members of this family are zinc-containing type II integral-membrane proteins that are important regulators of neuropeptide and peptide hormone activity. Mutations in this gene are associated with autosomal recessive distal arthrogryposis, type 5D. This gene has multiple pseudogenes on chromosome 2. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a disulfide_bond (size 254) in uniprot entity ECEL1_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_004826.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.912
PP5
Variant 2-232484198-G-A is Pathogenic according to our data. Variant chr2-232484198-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191152.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=2}. Variant chr2-232484198-G-A is described in Lovd as [Pathogenic]. Variant chr2-232484198-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ECEL1 | NM_004826.4 | c.1210C>T | p.Arg404Cys | missense_variant | Exon 7 of 18 | ENST00000304546.6 | NP_004817.2 | |
ECEL1 | NM_001290787.2 | c.1210C>T | p.Arg404Cys | missense_variant | Exon 7 of 18 | NP_001277716.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ECEL1 | ENST00000304546.6 | c.1210C>T | p.Arg404Cys | missense_variant | Exon 7 of 18 | 1 | NM_004826.4 | ENSP00000302051.1 | ||
ECEL1 | ENST00000409941.1 | c.1210C>T | p.Arg404Cys | missense_variant | Exon 6 of 17 | 1 | ENSP00000386333.1 | |||
ECEL1 | ENST00000482346.1 | n.1521C>T | non_coding_transcript_exon_variant | Exon 6 of 17 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248584Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134606
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460286Hom.: 0 Cov.: 33 AF XY: 0.00000826 AC XY: 6AN XY: 726396
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152292Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74462
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Distal arthrogryposis type 5D Pathogenic:3Uncertain:2
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 01, 2016 | - - |
Uncertain significance, criteria provided, single submitter | research | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Mar 14, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 01, 2020 | - - |
Likely pathogenic, no assertion criteria provided | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26752647, 23829171, 30131190) - |
Likely pathogenic, flagged submission | research | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Loss of MoRF binding (P = 0.0019);Loss of MoRF binding (P = 0.0019);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at