Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001399.5(EDA):c.628G>T(p.Gly210*) variant causes a stop gained change. 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 (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

EDA
NM_001399.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.15

Publications

0 publications found

Variant links:

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

EDA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-70027958-G-T is Pathogenic according to our data. Variant chrX-70027958-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 458660.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EDA	NM_001399.5	MANE Select	c.628G>T	p.Gly210*	stop_gained	Exon 4 of 8	NP_001390.1
EDA	NM_001005609.2		c.628G>T	p.Gly210*	stop_gained	Exon 4 of 8	NP_001005609.1
EDA	NM_001440761.1		c.628G>T	p.Gly210*	stop_gained	Exon 4 of 8	NP_001427690.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EDA	ENST00000374552.9	TSL:1 MANE Select	c.628G>T	p.Gly210*	stop_gained	Exon 4 of 8	ENSP00000363680.4
EDA	ENST00000374553.6	TSL:1	c.628G>T	p.Gly210*	stop_gained	Exon 4 of 8	ENSP00000363681.2
EDA	ENST00000524573.5	TSL:1	c.628G>T	p.Gly210*	stop_gained	Exon 4 of 8	ENSP00000432585.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1074807

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

349709

African (AFR)

AF:

0.00

AC:

AN:

25510

American (AMR)

AF:

0.00

AC:

AN:

32064

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18906

East Asian (EAS)

AF:

0.00

AC:

AN:

28665

South Asian (SAS)

AF:

0.00

AC:

AN:

51094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39115

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3909

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

830338

Other (OTH)

AF:

0.00

AC:

AN:

45206

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypohidrotic X-linked ectodermal dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

FATHMM_MKL

Pathogenic

0.99

PhyloP100

7.2

Vest4

0.94

GERP RS

4.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over