X-70033521-A-G

Position:

• chrX-70033521-A-G

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.917A>G​(p.Gln306Arg) 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. Q306H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 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, 0.984
• PP5: Variant X-70033521-A-G is Pathogenic according to our data. Variant chrX-70033521-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421976.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.917A>G	p.Gln306Arg	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>G	p.Gln306Arg	missense_variant	7/8	1	NM_001399.5	ENSP00000363680.4
EDA	ENST00000374553.6	c.917A>G	p.Gln306Arg	missense_variant, splice_region_variant	7/8	1		ENSP00000363681.2
EDA	ENST00000524573.5	c.908A>G	p.Gln303Arg	missense_variant, splice_region_variant	7/8	1		ENSP00000432585.1
EDA	ENST00000616899.1	c.521A>G	p.Gln174Arg	missense_variant	6/7	5		ENSP00000481963.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2016

The Q306R variant in the EDA gene has been reported previously in an individual with ectodermal dysplasia (Miyake et al., 2016). The Q306R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q306R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (Q306P) has been reported in association with hypohidrotic ectodermal dysplasia, and functional studies show this variant has an affect on cell proliferation and cell cycle distribution (Lei et al., 2009; Lei et al., 2016), supporting the functional importance of this residue. The Q306R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.73
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;D;.;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.61	T;D;T;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;M;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.7	D;N;D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0070	D;.;.;.
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.99	D;D;D;.
Vest4		0.96
MutPred		0.88		Gain of relative solvent accessibility (P = 0.2363);Gain of relative solvent accessibility (P = 0.2363);.;.;
MVP		1.0
MPC		1.9
ClinPred		0.98	D
GERP RS		5.5
Varity_R		1.0
gMVP		0.99

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;