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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.96
Variant links:
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

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EDANM_001399.5 linkc.553_588delAATGGCCCTCCAGGACCCCCAGGACCTCCAGGACCC p.Asn185_Pro196del conservative_inframe_deletion 4/8 ENST00000374552.9 NP_001390.1 Q92838-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EDAENST00000374552.9 linkc.553_588delAATGGCCCTCCAGGACCCCCAGGACCTCCAGGACCC p.Asn185_Pro196del conservative_inframe_deletion 4/81 NM_001399.5 ENSP00000363680.4 Q92838-1

Frequencies

GnomAD3 genomes
Cov.:
21
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
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 submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterDec 18, 2024- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 20, 2023For 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 31, 2013The 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 submitterclinical testingGeneDxOct 14, 2022In-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 submitterclinical testingAl Jalila Children’s Genomics Center, Al Jalila Childrens Speciality HospitalDec 17, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397516666; hg19: chrX-69247726; API