Variant X-69616319-C-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001399.5(EDA):c.11C>G(p.Pro4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000259 in 1,195,048 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000028 ( 0 hom. 14 hem. )

Consequence

EDA
NM_001399.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.37

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5 linkuse as main transcript	c.11C>G	p.Pro4Arg	missense_variant	1/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9 linkuse as main transcript	c.11C>G	p.Pro4Arg	missense_variant	1/8	1	NM_001399.5	P4	Q92838-1

Frequencies

GnomAD3 genomes

AF:

0.00000887

AC:

AN:

112785

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34937

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000277

AC:

AN:

1082263

Hom.:

Cov.:

AF XY:

0.0000394

AC XY:

AN XY:

355225

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:

0.0000334

Gnomad4 OTH exome

AF:

0.0000439

GnomAD4 genome

AF:

0.00000887

AC:

AN:

112785

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34937

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 27, 2022

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4 of the EDA protein (p.Pro4Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with EDA-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

Cadd

Benign

Dann

Uncertain

0.98

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.87

D;D;D;D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Uncertain

0.54

D;D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Benign

0.0

N;N;N;N;N;N

MutationTaster

Benign

0.56

N;N;N;N;N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.5

D;D;D;N;N;N

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

D;D;D;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;T;T;T

Polyphen

1.0

D;D;D;D;D;D

Vest4

0.23

MutPred

0.35

Gain of MoRF binding (P = 0.0011);Gain of MoRF binding (P = 0.0011);Gain of MoRF binding (P = 0.0011);Gain of MoRF binding (P = 0.0011);Gain of MoRF binding (P = 0.0011);Gain of MoRF binding (P = 0.0011);

MVP

0.99

MPC

0.83

ClinPred

0.89

GERP RS

4.6

Varity_R

0.33

gMVP

0.70

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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