X-66599555-C-A

Position:

chrX-66599555-C-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The ENST00000374719.8(EDA2R):c.823G>T(p.Gly275Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,188,189 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 78 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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. G275E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.00023 ( 0 hom. 73 hem. )

Consequence

EDA2R
ENST00000374719.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.491

Variant links:

Genes affected

EDA2R (HGNC:17756): (ectodysplasin A2 receptor) The protein encoded by this gene is a type III transmembrane protein of the TNFR (tumor necrosis factor receptor) superfamily, and contains cysteine-rich repeats and a single transmembrane domain. This protein binds to the EDA-A2 isoform of ectodysplasin, which plays an important role in maintenance of hair and teeth. Alternatively spliced transcript variants encodes distinct protein isoforms. [provided by RefSeq, Apr 2016]

EDA2R links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11104983).

BP6

Variant X-66599555-C-A is Benign according to our data. Variant chrX-66599555-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2358184.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA2R	NM_021783.5 linkuse as main transcript	c.823G>T	p.Gly275Trp	missense_variant	6/7	ENST00000374719.8	NP_068555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA2R	ENST00000374719.8 linkuse as main transcript	c.823G>T	p.Gly275Trp	missense_variant	6/7	1	NM_021783.5	ENSP00000363851	P1	Q9HAV5-1
EDA2R	ENST00000253392.5 linkuse as main transcript	c.886G>T	p.Gly296Trp	missense_variant	6/6	1		ENSP00000253392		Q9HAV5-2
EDA2R	ENST00000396050.5 linkuse as main transcript	c.886G>T	p.Gly296Trp	missense_variant	6/7	5		ENSP00000379365		Q9HAV5-2
EDA2R	ENST00000451436.6 linkuse as main transcript	c.823G>T	p.Gly275Trp	missense_variant	6/7	5		ENSP00000415242	P1	Q9HAV5-1

Frequencies

GnomAD3 genomes

AF:

0.000135

AC:

AN:

111142

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

AN XY:

33360

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:

0.000283

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000124

AC:

AN:

145361

Hom.:

AF XY:

0.0000920

AC XY:

AN XY:

43473

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000892

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000280

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000230

AC:

248

AN:

1077047

Hom.:

Cov.:

AF XY:

0.000209

AC XY:

AN XY:

349829

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000687

Gnomad4 SAS exome

AF:

0.0000195

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000289

Gnomad4 OTH exome

AF:

0.000110

GnomAD4 genome

AF:

0.000135

AC:

AN:

111142

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

AN XY:

33360

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:

0.000283

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000242

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000753

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.886G>T (p.G296W) alteration is located in exon 6 (coding exon 6) of the EDA2R gene. This alteration results from a G to T substitution at nucleotide position 886, causing the glycine (G) at amino acid position 296 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

EDA2R: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.37

CADD

Benign

6.7

DANN

Benign

0.95

DEOGEN2

Benign

0.12

T;.;T;.

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.71

.;T;T;.

M_CAP

Benign

0.080

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.55

N;.;N;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.76

N;.;.;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.022

D;.;.;D

Sift4G

Uncertain

0.057

T;T;T;T

Polyphen

0.66

P;P;P;P

Vest4

0.25

MVP

0.64

ClinPred

0.057

GERP RS

0.83

Varity_R

0.050

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Other links and lift over