chrX-70033398-A-G

Variant names:

• chrX-70033398-A-G
• rs727504750
• NM_001399.5:c.794A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_001399.5(EDA):​c.794A>G​(p.Asp265Gly) variant causes a missense, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D265A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: EDA NM_001399.5 missense, splice_region
• Scores: Splicing: ADA: 0.3884
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 8.72
• Publications: 3 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, Labcorp Genetics (formerly Invitae), Orphanet
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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, 0.755
• PP5: Variant X-70033398-A-G is Pathogenic according to our data. Variant chrX-70033398-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179264.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001399.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA	NM_001399.5	MANE Select	c.794A>G	p.Asp265Gly	missense splice_region	Exon 7 of 8	NP_001390.1	Q92838-1
	EDA	NM_001005609.2		c.794A>G	p.Asp265Gly	missense splice_region	Exon 7 of 8	NP_001005609.1	Q92838-3
	EDA	NM_001440762.1		c.794A>G	p.Asp265Gly	missense splice_region	Exon 7 of 8	NP_001427691.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA	ENST00000374552.9	TSL:1 MANE Select	c.794A>G	p.Asp265Gly	missense splice_region	Exon 7 of 8	ENSP00000363680.4	Q92838-1
	EDA	ENST00000374553.6	TSL:1	c.794A>G	p.Asp265Gly	missense splice_region	Exon 7 of 8	ENSP00000363681.2	Q92838-3
	EDA	ENST00000524573.5	TSL:1	c.794-9A>G		intron	N/A	ENSP00000432585.1	Q92838-9

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Hypohidrotic X-linked ectodermal dysplasia (2)
1	1	-	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.31	N
REVEL	Pathogenic	0.73
Sift	Benign	0.039	D
Sift4G	Benign	0.061	T
Polyphen		0.99	D
Vest4		0.92
MutPred		0.47		Gain of MoRF binding (P = 0.0502)
MVP		1.0
MPC		2.1
ClinPred		0.85	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.97
Mutation Taster		=26/74	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.39

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

Other links and lift over

dbSNP: rs727504750; hg19: chrX-69253248;