rs132630309

chrX-69616514-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69W) has been classified as Benign.

• 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:13
• Conservation: PhyloP100: 1.86

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]

ACMG classification

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_exome allele frequency = 0.00504 (5529/1097871) while in subpopulation NFE AF= 0.00607 (5112/842008). AF 95% confidence interval is 0.00593. There are 16 homozygotes in gnomad4_exome. There are 1735 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd at 89 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.206G>T	p.Arg69Leu	missense_variant	1/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.206G>T	p.Arg69Leu	missense_variant	1/8	1	NM_001399.5	P4

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 339 AN: 112284 Hom.: 1 Cov.: 24 AF XY: 0.00258 AC XY: 89 AN XY: 34438

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

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

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

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:2 Uncertain:2 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2019	This variant is associated with the following publications: (PMID: 8696334, 24631698, 26600092) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	EDA: PP3, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:2 Uncertain:2 Benign:2

Pathogenic, flagged submission	literature only	OMIM	Aug 01, 1996	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Pathogenic, flagged submission	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 03, 2015	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). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 17, 2023	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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2022

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
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
MutationTaster	Benign	0.44	A;A;A;A;A;A
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

Other links and lift over

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