chrX-70033426-G-T

Position:

• chrX-70033426-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_001399.5(EDA):​c.822G>T​(p.Trp274Cys) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W274G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.36

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant X-70033426-G-T is Pathogenic according to our data. Variant chrX-70033426-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44209.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.822G>T	p.Trp274Cys	missense_variant	7/8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.822G>T	p.Trp274Cys	missense_variant	7/8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 22, 2011

The Trp274Cys variant in EDA has not been reported in the literature nor previou sly identified by our laboratory. However, different amino acid changes at the s ame position (Trp274Gly, Trp274Arg) have been identified in 3 individuals with X -linked hypohidrotic ectodermal dysplasia (Paakkonen 2001, Schneider 2001, Cluze au 2011). In addition, this residue is conserved across species and computation al analyses (PolyPhen2, SIFT, AlignGVGD) suggest that the Trp274Cys variant may impact the protein. The change to a Cysteine at position 274 is likely to create an equal or greater impact to the protein than the other two missense mutations making it likely that this mutation is also pathogenic. In summary, this varia nt is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	.;D;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.6	L;L;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.2	D;D;D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0040	D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.99
MutPred		0.83		Loss of MoRF binding (P = 0.0154);Loss of MoRF binding (P = 0.0154);.;.;
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		1.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516675; hg19: chrX-69253276;