Genetic Variant EDA:p.Pro200Leu (chrX-70027929-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5

The NM_001399.5(EDA):c.599C>T(p.Pro200Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000936 in 1,068,003 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. P200Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 9.4e-7 ( 0 hom. 0 hem. )

Consequence

EDA
NM_001399.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.30

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001399.5

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-70027929-C-T is Pathogenic according to our data. Variant chrX-70027929-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3255519.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 link	c.599C>T	p.Pro200Leu	missense_variant	Exon 4 of 8	ENST00000374552.9	NP_001390.1	Q92838-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9 link	c.599C>T	p.Pro200Leu	missense_variant	Exon 4 of 8	1	NM_001399.5	ENSP00000363680.4		Q92838-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.36e-7

AC:

AN:

1068003

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

346479

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000121

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia

Pathogenic:1

Dental Genetics Laboratory, Seoul National University School of Dentistry

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

variation affecting protein function -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

.;D;.;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Uncertain

0.69

D;D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Benign

1.7

L;L;L;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.0

N;D;N;D;.

REVEL

Uncertain

0.54

Sift

Uncertain

0.0020

D;.;.;D;.

Sift4G

Uncertain

0.010

D;D;D;T;D

Polyphen

1.0

D;D;D;.;.

Vest4

0.58

MutPred

0.34

Loss of catalytic residue at P199 (P = 0.0317);Loss of catalytic residue at P199 (P = 0.0317);Loss of catalytic residue at P199 (P = 0.0317);.;.;

MVP

0.96

MPC

0.80

ClinPred

0.85

GERP RS

4.7

Varity_R

0.85

gMVP

0.91

Splicing

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over