chrX-69957097-G-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3PP5_Moderate
The NM_001399.5(EDA):c.467G>T(p.Arg156Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156C) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 23)
Consequence
EDA
NM_001399.5 missense
NM_001399.5 missense
Scores
4
9
4
Clinical Significance
Conservation
PhyloP100: 5.55
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 Likely_pathogenic. Variant got 9 ACMG points.
PM1
In a region_of_interest Disordered (size 99) in uniprot entity EDA_HUMAN there are 53 pathogenic changes around while only 7 benign (88%) in NM_001399.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-69957096-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.805
PP5
Variant X-69957097-G-T is Pathogenic according to our data. Variant chrX-69957097-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 44194.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-69957097-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EDA | NM_001399.5 | c.467G>T | p.Arg156Leu | missense_variant | 2/8 | ENST00000374552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDA | ENST00000374552.9 | c.467G>T | p.Arg156Leu | missense_variant | 2/8 | 1 | NM_001399.5 | P4 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 03, 2015 | The p.Arg156Leu variant in EDA has been reported in 1 adult male with X-linked h ypohidrotic ectodermal dysplasia (XLHED; Dietz 2013), and was absent from large population studies. In addition, several variants affecting the same amino acid position (p.Arg156His, p.Arg156Cys, p.Arg156Gly, p.Arg156Ser) have been identifi ed in multiple individuals with X-linked hypohidrotic ectodermal dysplasia and s egregated with disease in those families, suggesting that the arginine (Arg) res idue at position 156 is intolerant to variation (Monreal 1998, Aoki 2000, Schnei der 2001, Vincent 2001, Schneider 2011, Zhao 2008, Cluzeau 2011, Clauss 2010, Li 2013, He 2013, Dietz 2013). In vitro functional studies provide evidence that a change affecting this amino acid position disrupts the normal processing and fu nction of the EDA protein (Chen 2001), consistent with a causal role for variant s identified at this position. In summary, this variant meets our criteria to be classified as pathogenic for X-linked hypohidrotic ectodermal dysplasia (http:/ /www.partners.org/personalizedmedicine/LMM) based upon the presence of this vari ant as well as other variants affecting the same position in several affected in dividuals, and the functional evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;T;.;.;.
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;.
REVEL
Uncertain
Sift
Uncertain
D;.;.;D;.
Sift4G
Benign
T;T;T;T;D
Polyphen
P;P;D;.;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0449);Loss of MoRF binding (P = 0.0449);Loss of MoRF binding (P = 0.0449);.;.;
MVP
MPC
0.97
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at