rs132630320

Variant names:

• chrX-70035505-C-G
• rs132630320
• NM_001399.5:c.1072C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_001399.5(EDA):​c.1072C>G​(p.Gln358Glu) 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q358R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.29
• Publications: 9 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.923
• PP5: Variant X-70035505-C-G is Pathogenic according to our data. Variant chrX-70035505-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 11045.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.1072C>G	p.Gln358Glu	missense_variant	Exon 8 of 8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.1072C>G	p.Gln358Glu	missense_variant	Exon 8 of 8	1	NM_001399.5	ENSP00000363680.4
EDA	ENST00000374553.6	c.1066C>G	p.Gln356Glu	missense_variant	Exon 8 of 8	1		ENSP00000363681.2
EDA	ENST00000524573.5	c.1057C>G	p.Gln353Glu	missense_variant	Exon 8 of 8	1		ENSP00000432585.1
EDA	ENST00000616899.1	c.676C>G	p.Gln226Glu	missense_variant	Exon 7 of 7	5		ENSP00000481963.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Tooth agenesis, selective, X-linked, 1 Pathogenic:1

Feb 15, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	.;D;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.69	.;N;.;.
PhyloP100		7.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.37	N;N;N;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Benign	0.062	T;T;T;T
Polyphen		0.98	D;D;D;.
Vest4		0.83
MutPred		0.81		.;Loss of catalytic residue at Q358 (P = 0.0079);.;.;
MVP		1.0
MPC		1.8
ClinPred		0.81	D
GERP RS		5.4
Varity_R		0.90
gMVP		0.97
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs132630320; hg19: chrX-69255355;