X-70035560-A-G
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_001399.5(EDA):c.1127A>G(p.His376Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 21)
Consequence
EDA
NM_001399.5 missense
NM_001399.5 missense
Scores
10
3
2
Clinical Significance
Conservation
PhyloP100: 8.62
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 Uncertain_significance. Variant got 5 ACMG points.
PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_001399.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.838
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EDA | NM_001399.5 | c.1127A>G | p.His376Arg | missense_variant | 8/8 | ENST00000374552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDA | ENST00000374552.9 | c.1127A>G | p.His376Arg | missense_variant | 8/8 | 1 | NM_001399.5 | P4 | |
EDA | ENST00000374553.6 | c.1121A>G | p.His374Arg | missense_variant | 8/8 | 1 | A1 | ||
EDA | ENST00000524573.5 | c.1112A>G | p.His371Arg | missense_variant | 8/8 | 1 | A1 | ||
EDA | ENST00000616899.1 | c.731A>G | p.His244Arg | missense_variant | 7/7 | 5 |
Frequencies
GnomAD3 genomes Cov.: 21
GnomAD3 genomes
Cov.:
21
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 21
GnomAD4 genome
Cov.:
21
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 18, 2016 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.His376Arg variant in EDA has not been previously reported in individuals with hypohidroti c ectodermal dysplasia (HED) and was absent from large population studies. Comp utational prediction tools and conservation analyses suggest that this variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. In summary, while there is some suspicion for a pathogenic r ole, the clinical significance of this variant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;.
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;D;.
Vest4
MutPred
0.54
.;Gain of MoRF binding (P = 0.017);.;.;
MVP
MPC
2.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at