rs1341894581

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_004826.4(ECEL1):c.110_155delTCCCGTTGGGCGCTGCGCGCAGCGCCACCGGGGCCCGGTCCGGGCT(p.Phe37CysfsTer151) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000571 in 1,383,780 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

ECEL1
NM_004826.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.70

Publications

3 publications found

Variant links:

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]

ECEL1 Gene-Disease associations (from GenCC):

distal arthrogryposis type 5D
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ECEL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 2-232486498-CAGCCCGGACCGGGCCCCGGTGGCGCTGCGCGCAGCGCCCAACGGGA-C is Pathogenic according to our data. Variant chr2-232486498-CAGCCCGGACCGGGCCCCGGTGGCGCTGCGCGCAGCGCCCAACGGGA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 435024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4 link	c.110_155delTCCCGTTGGGCGCTGCGCGCAGCGCCACCGGGGCCCGGTCCGGGCT	p.Phe37CysfsTer151	frameshift_variant	Exon 2 of 18	ENST00000304546.6	NP_004817.2	O95672-1A0A6F7YIA8
ECEL1	NM_001290787.2 link	c.110_155delTCCCGTTGGGCGCTGCGCGCAGCGCCACCGGGGCCCGGTCCGGGCT	p.Phe37CysfsTer151	frameshift_variant	Exon 2 of 18		NP_001277716.1	O95672-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ECEL1	ENST00000304546.6 link	c.110_155delTCCCGTTGGGCGCTGCGCGCAGCGCCACCGGGGCCCGGTCCGGGCT	p.Phe37CysfsTer151	frameshift_variant	Exon 2 of 18	1	NM_004826.4	ENSP00000302051.1	O95672-1
ECEL1	ENST00000409941.1 link	c.110_155delTCCCGTTGGGCGCTGCGCGCAGCGCCACCGGGGCCCGGTCCGGGCT	p.Phe37CysfsTer151	frameshift_variant	Exon 1 of 17	1		ENSP00000386333.1	O95672-2
ECEL1	ENST00000482346.1 link	n.314_359delTCCCGTTGGGCGCTGCGCGCAGCGCCACCGGGGCCCGGTCCGGGCT		non_coding_transcript_exon_variant	Exon 2 of 17	2

Frequencies

GnomAD3 genomes

AF:

0.000106

AC:

AN:

151644

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000737

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000326

AC:

AN:

21450

AF XY:

0.000299

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00195

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000215

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000511

AC:

AN:

1232136

Hom.:

AF XY:

0.0000431

AC XY:

AN XY:

602972

show subpopulations

African (AFR)

AF:

0.0000417

AC:

AN:

23970

American (AMR)

AF:

0.000750

AC:

AN:

11998

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18550

East Asian (EAS)

AF:

0.0000367

AC:

AN:

27260

South Asian (SAS)

AF:

0.00

AC:

AN:

55072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29944

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3548

European-Non Finnish (NFE)

AF:

0.0000494

AC:

AN:

1011176

Other (OTH)

AF:

0.0000395

AC:

AN:

50618

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000106

AC:

AN:

151644

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74044

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41368

American (AMR)

AF:

0.000394

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000737

AC:

AN:

67882

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000253

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Distal arthrogryposis type 5D

Pathogenic:4

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with distal arthrogryposis, type 5D (MIM#615065). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v3) for a recessive condition (16 heterozygotes, 0 homozygotes). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are multiple NMD-predicted variants that have been classified as likely pathogenic or pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been identified in individuals with distal arthrogryposis (ClinVar; PMIDs: 30792901, 33966749, 33060286). (SP) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a heterozygous likely pathogenic variant, NM_004826.3(ECEL1):c.1783_1788del, p.(Pro595Asp596del), in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 05, 2016

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2019

Genomic Medicine Lab, University of California San Francisco

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jan 17, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Jun 03, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in the presence of a second ECEL1 variant in a patient with arthrogryposis (Scocchia et al., 2019); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23236030, 23261301, 25099528, 24782201, 25708584, 33743358, 33966749, 30792901, 27535533) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.7

Mutation Taster

=52/148

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over