rs397516666
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM4PP3PP5_Very_Strong
The NM_001399.5(EDA):c.553_588delAATGGCCCTCCAGGACCCCCAGGACCTCCAGGACCC(p.Asn185_Pro196del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 21)
Consequence
EDA
NM_001399.5 conservative_inframe_deletion
NM_001399.5 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.96
Genes affected
EDA (HGNC:3157): (ectodysplasin A) The protein encoded by this gene is a type II membrane protein that can be cleaved by furin to produce a secreted form. The encoded protein, which belongs to the tumor necrosis factor family, acts as a homotrimer and may be involved in cell-cell signaling during the development of ectodermal organs. Defects in this gene are a cause of ectodermal dysplasia, anhidrotic, which is also known as X-linked hypohidrotic ectodermal dysplasia. Several transcript variants encoding many different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM1
In a domain Collagen-like (size 49) in uniprot entity EDA_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001399.5
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001399.5.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant X-70027876-TGGACCCAATGGCCCTCCAGGACCCCCAGGACCTCCA-T is Pathogenic according to our data. Variant chrX-70027876-TGGACCCAATGGCCCTCCAGGACCCCCAGGACCTCCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 44198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70027876-TGGACCCAATGGCCCTCCAGGACCCCCAGGACCTCCA-T is described in Lovd as [Pathogenic]. Variant chrX-70027876-TGGACCCAATGGCCCTCCAGGACCCCCAGGACCTCCA-T is described in Lovd as [Pathogenic]. Variant chrX-70027876-TGGACCCAATGGCCCTCCAGGACCCCCAGGACCTCCA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 21
GnomAD3 genomes
Cov.:
21
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 21
GnomAD4 genome
Cov.:
21
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypohidrotic X-linked ectodermal dysplasia Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Dec 18, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 20, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 44198). This variant is also known as Del794–829 or 789/795del36. This variant has been observed in individual(s) with hypohidrotic ectodermal dysplasia (PMID: 9683615, 9736768, 18231121). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.553_588del, results in the deletion of 12 amino acid(s) of the EDA protein (p.Asn185_Pro196del), but otherwise preserves the integrity of the reading frame. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 31, 2013 | The p.Asn185_Pro196del variant in EDA has been identified in several individuals with clinical features of X-linked hypohidrotic ectodermal dysplasia (Bayes 199 8, Monreal 1998, Schneider 2001, Lexner 2008, Schneider 2011). Some of these ind ividuals were reported to have the c.553_588del variant, as seen in this individ ual, while others were reported to have the c.546_581del variant. Both variants result in the same amino acid deletion, and therefore likely have the same impac t to the protein. Non-standard nomenclature has been also used in some reports ( c.del794-829). The variant has been identified in one carrier mother and her two affected sons, as well as de novo in at least 2 individuals with de novo diseas e (Monreal 1998, Scheinder 2001). In summary, this variant meets our criteria to be classified as pathogenic for HED in an X-linked manner (http://www.partners. org/personalizedmedicine/LMM). - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 14, 2022 | In-frame deletion of 12 amino acids in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11279189, 31796081, 18510547, 9736768, 21357618, 9683615) - |
Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 17, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at