X-70033521-A-T

Position:

• chrX-70033521-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001399.5(EDA):​c.917A>T​(p.Gln306Leu) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q306H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.72

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 Likely_pathogenic. Variant got 8 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, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.917A>T	p.Gln306Leu	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.917A>T	p.Gln306Leu	missense_variant	7/8	1	NM_001399.5	ENSP00000363680.4
EDA	ENST00000374553.6	c.917A>T	p.Gln306Leu	missense_variant, splice_region_variant	7/8	1		ENSP00000363681.2
EDA	ENST00000524573.5	c.908A>T	p.Gln303Leu	missense_variant, splice_region_variant	7/8	1		ENSP00000432585.1
EDA	ENST00000616899.1	c.521A>T	p.Gln174Leu	missense_variant	6/7	5		ENSP00000481963.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 24, 2014

Variant classified as Uncertain Significance - Favor Pathogenic. The Gln306Leu v ariant in EDA has not been previously reported in any individuals with X-linked hypohidrotic ectodermal dysplasia (XLHED) and was absent from large population s tudies. However, two other amino acid changes (Gln306His and Gln306Pro) at this position have been reported in individual with XLHED (Hsu 2003, Lei 2009), sugg esting that changes at this position may not be tolerated. Computational predict ion tools and conservation analysis suggest that the Gln306Leu variant may impac t the protein, though this information is not predictive enough to determine pat hogenicity. In summary, while the available data on the Gln306Leu variant is sus picious to be pathogenic, the clinical significance of this variant is uncertain . -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;.;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.60	T;D;T;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;M;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.7	D;D;D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0040	D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.99	D;D;D;.
Vest4		0.93
MutPred		0.85		Loss of phosphorylation at Y301 (P = 0.3439);Loss of phosphorylation at Y301 (P = 0.3439);.;.;
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		1.0
gMVP		0.98

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503009; hg19: chrX-69253371;