rs727503009

Variant names:

• chrX-70033521-A-C
• NM_001399.5:c.917A>C

Your query was ambiguous. Multiple possible variants found:

• chrX-70033521-A-C
• chrX-70033521-A-G
• chrX-70033521-A-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.917A>C​(p.Gln306Pro) 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 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: 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, 0.991
• PP5: Variant X-70033521-A-C is Pathogenic according to our data. Variant chrX-70033521-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2138596.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.917A>C	p.Gln306Pro	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.917A>C	p.Gln306Pro	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: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Mar 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 306 of the EDA protein (p.Gln306Pro). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. This variant is also known as c.907A>C. This missense change has been observed in individuals with ectodermal dysplasia (PMID: 20077893; Invitae). This variant disrupts the p.Gln306 amino acid residue in EDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27264909; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	.;D;.;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.66	T;D;T;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;M;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.0	D;D;D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0060	D;.;.;.
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.98
MutPred		0.94		Loss of catalytic residue at Q306 (P = 0.0201);Loss of catalytic residue at Q306 (P = 0.0201);.;.;
MVP		1.0
MPC		2.1
ClinPred		0.99	D
GERP RS		5.5
Varity_R		1.0
gMVP		1.0

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-69253371;