X-69616309-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_001399.5(EDA):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-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 Pathogenic (★).

Frequency

Genomes: not found (cov: 24)

Consequence

EDA
NM_001399.5 start_lost

Scores

8
3
3

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.45
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 Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 396 CDS bases. Genomic position: 69616704. Lost 0.337 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-69616309-A-G is Pathogenic according to our data. Variant chrX-69616309-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1070893.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EDANM_001399.5 linkc.1A>G p.Met1? start_lost Exon 1 of 8 ENST00000374552.9 NP_001390.1 Q92838-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EDAENST00000374552.9 linkc.1A>G p.Met1? start_lost Exon 1 of 8 1 NM_001399.5 ENSP00000363680.4 Q92838-1

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1
Oct 14, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Disruption of the initiator codon has been observed in individual(s) with ectodermal dysplasia (PMID: 24330993, 18076698, 20979233, 11378824). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the EDA mRNA. The next in-frame methionine is located at codon 133. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Benign
0.33
.;.;.;.;T;.
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.90
D;D;D;D;D;D
M_CAP
Pathogenic
1.0
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D
MetaSVM
Pathogenic
0.96
D
PROVEAN
Benign
-1.3
N;N;N;N;N;N
REVEL
Pathogenic
0.66
Sift
Pathogenic
0.0
D;D;D;D;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
0.86
P;P;P;B;B;B
Vest4
0.84
MutPred
0.99
Loss of solvent accessibility (P = 0.3103);Loss of solvent accessibility (P = 0.3103);Loss of solvent accessibility (P = 0.3103);Loss of solvent accessibility (P = 0.3103);Loss of solvent accessibility (P = 0.3103);Loss of solvent accessibility (P = 0.3103);
MVP
1.0
ClinPred
0.99
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.61
gMVP
0.88

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-68836153; API