rs132630309

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001399.5(EDA):​c.206G>T​(p.Arg69Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00485 in 1,210,205 control chromosomes in the GnomAD database, including 17 homozygotes. There are 1,824 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., 89 hem., cov: 24)
Exomes 𝑓: 0.0050 ( 16 hom. 1735 hem. )

Consequence

EDA
NM_001399.5 missense

Scores

7
4
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2B:13

Conservation

PhyloP100: 1.86
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.023254514).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00301 (338/112334) while in subpopulation NFE AF= 0.00538 (285/53015). AF 95% confidence interval is 0.00486. There are 1 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Hemizygotes in GnomAd4 at 89 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EDANM_001399.5 linkc.206G>T p.Arg69Leu missense_variant 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.206G>T p.Arg69Leu missense_variant Exon 1 of 8 1 NM_001399.5 ENSP00000363680.4 Q92838-1

Frequencies

GnomAD3 genomes
AF:
0.00302
AC:
339
AN:
112284
Hom.:
1
Cov.:
24
AF XY:
0.00258
AC XY:
89
AN XY:
34438
show subpopulations
Gnomad AFR
AF:
0.000581
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00185
Gnomad ASJ
AF:
0.00151
Gnomad EAS
AF:
0.000285
Gnomad SAS
AF:
0.00189
Gnomad FIN
AF:
0.000320
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00537
Gnomad OTH
AF:
0.00264
GnomAD3 exomes
AF:
0.00286
AC:
519
AN:
181348
Hom.:
1
AF XY:
0.00302
AC XY:
201
AN XY:
66662
show subpopulations
Gnomad AFR exome
AF:
0.000997
Gnomad AMR exome
AF:
0.000841
Gnomad ASJ exome
AF:
0.00255
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00136
Gnomad FIN exome
AF:
0.000694
Gnomad NFE exome
AF:
0.00517
Gnomad OTH exome
AF:
0.00267
GnomAD4 exome
AF:
0.00504
AC:
5529
AN:
1097871
Hom.:
16
Cov.:
32
AF XY:
0.00477
AC XY:
1735
AN XY:
363367
show subpopulations
Gnomad4 AFR exome
AF:
0.00110
Gnomad4 AMR exome
AF:
0.000852
Gnomad4 ASJ exome
AF:
0.00279
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00159
Gnomad4 FIN exome
AF:
0.000892
Gnomad4 NFE exome
AF:
0.00607
Gnomad4 OTH exome
AF:
0.00369
GnomAD4 genome
AF:
0.00301
AC:
338
AN:
112334
Hom.:
1
Cov.:
24
AF XY:
0.00258
AC XY:
89
AN XY:
34500
show subpopulations
Gnomad4 AFR
AF:
0.000580
Gnomad4 AMR
AF:
0.00176
Gnomad4 ASJ
AF:
0.00151
Gnomad4 EAS
AF:
0.000286
Gnomad4 SAS
AF:
0.00189
Gnomad4 FIN
AF:
0.000320
Gnomad4 NFE
AF:
0.00538
Gnomad4 OTH
AF:
0.00261
Alfa
AF:
0.00376
Hom.:
23
Bravo
AF:
0.00296
TwinsUK
AF:
0.00324
AC:
12
ALSPAC
AF:
0.00450
AC:
13
ESP6500AA
AF:
0.00130
AC:
5
ESP6500EA
AF:
0.00550
AC:
37
ExAC
AF:
0.00321
AC:
390
EpiCase
AF:
0.00502
EpiControl
AF:
0.00439

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2Benign:13
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:7
Nov 22, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 15, 2019
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 8696334, 24631698, 26600092) -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 05, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

EDA: PP3, BS2 -

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:2Uncertain:2Benign:2
Jan 17, 2020
Natera, Inc.
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 03, 2017
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Pathogenic
Review Status: flagged submission
Collection Method: clinical testing

- -

Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 01, 1996
OMIM
Significance: Pathogenic
Review Status: flagged submission
Collection Method: literature only

- -

May 18, 2021
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:3
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 03, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Arg69Leu in exon 1 of EDA: This variant has been reported in 5 probands with X LHED, one of whom also carried a pathogenic variant in the same gene (Kere1996, Vincent 2001, Schneider 2011, Dietz 2013). However, this variant is not expected to have clinical significance because it has been identified in 0.5% (231/47072 ) of European chromosomes (94 hemizygotes) by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs132630309). -

Feb 17, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: EDA c.206G>T (p.Arg69Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 181348 control chromosomes in the gnomAD database, including 201 hemizygotes and 1 homozygote. The high occurrence of hemizygotes suggests that the variant is benign. Although the variant, c.206G>T, has been reported in the literature in individuals affected with Hypohidrotic Ectodermal Dysplasia or related phenotypes (e.g. Kere_1996, Vincent_2001, Stagi_2009, Schneider_2011, Dietz_2013, Bonds_2014, Burger_2014, Ferstl_2018), however, no evidence for cosegregation was reported. In addition, in some of these cases co-occurrences with other pathogenic variants have been reported, which could explain the phenotype (EDA c.991C>T (p.Gln331Ter), Dietz_2013; EDA c.467G>A (p.Arg156His), Stagi_2009; TP63 c.952C>T (p.Arg318Cys), Ferstl_2018), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including pathogenic (n=1), uncertain significance (n=2), and benign (n=4) / likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -

EDA-related disorder Benign:1
Jun 14, 2022
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Uncertain
0.045
T
BayesDel_noAF
Pathogenic
0.29
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.54
.;.;.;.;D;.
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.79
T;T;T;T;T;T
M_CAP
Pathogenic
0.81
D
MetaRNN
Benign
0.023
T;T;T;T;T;T
MetaSVM
Pathogenic
0.82
D
MutationAssessor
Benign
0.81
L;L;L;L;L;L
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-6.3
D;D;D;N;N;N
REVEL
Pathogenic
0.72
Sift
Benign
0.084
T;T;T;D;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
1.0
D;D;B;P;P;P
Vest4
0.16
MVP
1.0
MPC
0.97
ClinPred
0.050
T
GERP RS
3.2
Varity_R
0.54
gMVP
0.71

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: rs132630309; hg19: chrX-68836358; COSMIC: COSV58877505; COSMIC: COSV58877505; API