X-69957097-G-T

Variant names:

• chrX-69957097-G-T
• rs132630314
• NM_001399.5:c.467G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_001399.5(EDA):​c.467G>T​(p.Arg156Leu) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.55
• Publications: 28 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 1 uncertain in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-69957097-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.805
• PP5: Variant X-69957097-G-T is Pathogenic according to our data. Variant chrX-69957097-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 44194.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.467G>T	p.Arg156Leu	missense_variant	Exon 2 of 8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.467G>T	p.Arg156Leu	missense_variant	Exon 2 of 8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Mar 03, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg156Leu variant in EDA has been reported in 1 adult male with X-linked h ypohidrotic ectodermal dysplasia (XLHED; Dietz 2013), and was absent from large population studies. In addition, several variants affecting the same amino acid position (p.Arg156His, p.Arg156Cys, p.Arg156Gly, p.Arg156Ser) have been identifi ed in multiple individuals with X-linked hypohidrotic ectodermal dysplasia and s egregated with disease in those families, suggesting that the arginine (Arg) res idue at position 156 is intolerant to variation (Monreal 1998, Aoki 2000, Schnei der 2001, Vincent 2001, Schneider 2011, Zhao 2008, Cluzeau 2011, Clauss 2010, Li 2013, He 2013, Dietz 2013). In vitro functional studies provide evidence that a change affecting this amino acid position disrupts the normal processing and fu nction of the EDA protein (Chen 2001), consistent with a causal role for variant s identified at this position. In summary, this variant meets our criteria to be classified as pathogenic for X-linked hypohidrotic ectodermal dysplasia (http:/ /www.partners.org/personalizedmedicine/LMM) based upon the presence of this vari ant as well as other variants affecting the same position in several affected in dividuals, and the functional evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;T;.;.;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.90	L;L;L;.;.
PhyloP100		5.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.8	N;N;N;N;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.016	D;.;.;D;.
Sift4G	Benign	0.30	T;T;T;T;D
Polyphen		0.94	P;P;D;.;.
Vest4		0.67
MutPred		0.69		Loss of MoRF binding (P = 0.0449);Loss of MoRF binding (P = 0.0449);Loss of MoRF binding (P = 0.0449);.;.;
MVP		0.98
MPC		0.97
ClinPred		0.81	D
GERP RS		5.0
PromoterAI		-0.027	Neutral
Varity_R		0.77
gMVP		0.94
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs132630314; hg19: chrX-69176947;