X-70033398-A-G

Variant names:

• chrX-70033398-A-G
• rs727504750
• NM_001399.5:c.794A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_001399.5(EDA):​c.794A>G​(p.Asp265Gly) variant causes a missense, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. D265A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: EDA NM_001399.5 missense, splice_region
• Scores: Splicing: ADA: 0.3884
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 8.72
• Publications: 3 publications found

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]

EDA Gene-Disease associations (from GenCC):

• tooth agenesis, selective, X-linked, 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• X-linked hypohidrotic ectodermal dysplasia

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 1.7843 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to tooth agenesis, selective, X-linked, 1, X-linked hypohidrotic ectodermal dysplasia, tooth agenesis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755
• PP5: Variant X-70033398-A-G is Pathogenic according to our data. Variant chrX-70033398-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179264.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.794A>G	p.Asp265Gly	missense_variant, splice_region_variant	Exon 7 of 8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.794A>G	p.Asp265Gly	missense_variant, splice_region_variant	Exon 7 of 8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Pathogenic:1 Uncertain:1

Oct 31, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Asp265Gly variant in EDA has not been previously reported in individuals wit h ectodermal dysplasia or in large population studies. A different amino acid ch ange at this position (Arg265Asn) has been seen in one individual with clinical features of ectodermal dysplasia by our laboratory, but it is unclear if that va riant was the cause of the clinical features. The aspartic acid (Asp) residue at position 265 is highly conserved across mammals and evolutionarily distant spec ies, suggesting that a change to the amino acid may not be tolerated. In additio n, computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhe n2, and SIFT) suggest that the Asp265Gly variant may impact the protein. Alterna tively, although this variant is located in the first base of the exon, which is part of the 5? splice consensus region, computational tools do not predict alte red splicing. However, the accuracy of these predicative tools is unknown and th erefore, not predictive enough to assume or rule out pathogenicity. In summary, additional information is needed to fully assess the clinical significance of th e Asp265Gly variant. -

Sep 07, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1 Uncertain:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 265 of the EDA protein (p.Asp265Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypohidrotic ectodermal dysplasia (PMID: 25333067; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 179264). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Feb 17, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4_MOD,PM2_SUP,PP1,PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;M;.;.
PhyloP100		8.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.31	N;N;N;.
REVEL	Pathogenic	0.73
Sift	Benign	0.039	D;.;D;.
Sift4G	Benign	0.061	T;D;D;T
Polyphen		0.99	D;D;.;.
Vest4		0.92
MutPred		0.47		Gain of MoRF binding (P = 0.0502);Gain of MoRF binding (P = 0.0502);.;.;
MVP		1.0
MPC		2.1
ClinPred		0.85	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.97
Mutation Taster		=26/74	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.39

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

Other links and lift over

dbSNP: rs727504750; hg19: chrX-69253248;