Variant X-66604490-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_021783.5(EDA2R):c.283C>T(p.Arg95Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,206,124 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000027 ( 0 hom. 9 hem. )

Consequence

EDA2R
NM_021783.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.67

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.073266745).

BS2

High Hemizygotes in GnomAdExome4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA2R	NM_021783.5 link	c.283C>T	p.Arg95Cys	missense_variant	Exon 4 of 7	ENST00000374719.8	NP_068555.2	Q9HAV5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EDA2R	ENST00000374719.8 link	c.283C>T	p.Arg95Cys	missense_variant	Exon 4 of 7	1	NM_021783.5	ENSP00000363851.3	Q9HAV5-1
EDA2R	ENST00000253392.5 link	c.283C>T	p.Arg95Cys	missense_variant	Exon 3 of 6	1		ENSP00000253392.5	Q9HAV5-2
EDA2R	ENST00000396050.5 link	c.283C>T	p.Arg95Cys	missense_variant	Exon 3 of 7	5		ENSP00000379365.2	Q9HAV5-2
EDA2R	ENST00000451436.6 link	c.283C>T	p.Arg95Cys	missense_variant	Exon 4 of 7	5		ENSP00000415242.3	Q9HAV5-1

Frequencies

GnomAD3 genomes

AF:

0.0000358

AC:

AN:

111648

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33798

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000382

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000443

AC:

AN:

180743

Hom.:

AF XY:

0.0000459

AC XY:

AN XY:

65401

show subpopulations

Gnomad AFR exome

AF:

0.0000765

Gnomad AMR exome

AF:

0.0000373

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000733

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000247

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1094476

Hom.:

Cov.:

AF XY:

0.0000250

AC XY:

AN XY:

360262

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.0000285

Gnomad4 ASJ exome

AF:

0.0000518

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.000244

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000358

AC:

AN:

111648

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33798

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000382

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.283C>T (p.R95C) alteration is located in exon 3 (coding exon 3) of the EDA2R gene. This alteration results from a C to T substitution at nucleotide position 283, causing the arginine (R) at amino acid position 95 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.45

T;.;T;.

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.83

.;T;T;.

M_CAP

Benign

0.0088

MetaRNN

Benign

0.073

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.49

N;N;N;N

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.6

D;D;.;D

REVEL

Benign

0.065

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Benign

0.082

T;T;T;T

Polyphen

0.10

B;B;B;B

Vest4

0.41

MVP

0.63

ClinPred

0.15

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.38

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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