rs397516678

Variant names:

• chrX-70033485-A-T
• rs397516678
• NM_001399.5:c.881A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_001399.5(EDA):​c.881A>T​(p.Glu294Val) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.83
• Publications: 0 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 8 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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, 0.859
• PP5: Variant X-70033485-A-T is Pathogenic according to our data. Variant chrX-70033485-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44212.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.881A>T	p.Glu294Val	missense_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.881A>T	p.Glu294Val	missense_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:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Aug 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EDA protein function. ClinVar contains an entry for this variant (Variation ID: 44212). This missense change has been observed in individual(s) with clinical features of ectodermal dysplasia (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 294 of the EDA protein (p.Glu294Val). -

not specified Uncertain:1

Aug 21, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Gly294Val v ariant has been identified in a male individual with the clinical features of X- linked hypohidrotic ectodermal dysplasia (XL-HED) by our laboratory and the vari ant was also detected in the individual's affected maternal grandfather and moth er. Computational prediction tools and conservation analysis suggest that the Gl u294Val variant may impact the protein, though this information is not predictiv e enough to determine pathogenicity. Several other variants causative for X-lin ked hypohidrotic ectodermal dysplasia are found in this region of the EDA protei n, suggesting that this variant is more likely to impact protein function. In s ummary, while there is some suspicion for a pathogenic role, the clinical signif icance of the Glu294Val variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;D;.;.
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	0.10	N;N;.;.
PhyloP100		6.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.4	N;N;N;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D;.;.;.
Sift4G	Uncertain	0.028	D;D;T;D
Polyphen		1.0	D;D;D;.
Vest4		0.68
MutPred		0.57		Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);.;.;
MVP		1.0
MPC		1.4
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.92
Mutation Taster		=22/78	disease causing

Splicing

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

Other links and lift over

dbSNP: rs397516678; hg19: chrX-69253335;