Genetic Variant NM_021783.5:c.275G>A (chrX-66604498-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_021783.5(EDA2R):c.275G>A(p.Arg92Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,205,394 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 72 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., 7 hem., cov: 22)

Exomes 𝑓: 0.00018 ( 0 hom. 65 hem. )

Consequence

EDA2R
NM_021783.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.516

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

X-linked hypohidrotic ectodermal dysplasia
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

EDA2R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06443906).

BP6

Variant X-66604498-C-T is Benign according to our data. Variant chrX-66604498-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2266329.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021783.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDA2R	NM_021783.5	MANE Select	c.275G>A	p.Arg92Gln	missense	Exon 4 of 7	NP_068555.2	Q9HAV5-1
EDA2R	NM_001242310.1		c.275G>A	p.Arg92Gln	missense	Exon 3 of 7	NP_001229239.1	Q9HAV5
EDA2R	NM_001324206.2		c.275G>A	p.Arg92Gln	missense	Exon 4 of 7	NP_001311135.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDA2R	ENST00000374719.8	TSL:1 MANE Select	c.275G>A	p.Arg92Gln	missense	Exon 4 of 7	ENSP00000363851.3	Q9HAV5-1
EDA2R	ENST00000253392.5	TSL:1	c.275G>A	p.Arg92Gln	missense	Exon 3 of 6	ENSP00000253392.5	Q9HAV5-2
EDA2R	ENST00000396050.5	TSL:5	c.275G>A	p.Arg92Gln	missense	Exon 3 of 7	ENSP00000379365.2	Q9HAV5-2

Frequencies

GnomAD3 genomes

AF:

0.000206

AC:

AN:

111590

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000378

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00844

Gnomad NFE

AF:

0.000358

Gnomad OTH

AF:

0.000669

GnomAD2 exomes

AF:

0.000255

AC:

AN:

180480

AF XY:

0.000292

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000373

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000458

Gnomad OTH exome

AF:

0.000907

GnomAD4 exome

AF:

0.000183

AC:

200

AN:

1093754

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

AN XY:

359576

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26326

American (AMR)

AF:

0.0000285

AC:

AN:

35045

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19264

East Asian (EAS)

AF:

0.00

AC:

AN:

30119

South Asian (SAS)

AF:

0.000188

AC:

AN:

53120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40412

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

4117

European-Non Finnish (NFE)

AF:

0.000192

AC:

161

AN:

839459

Other (OTH)

AF:

0.000283

AC:

AN:

45892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000206

AC:

AN:

111640

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

AN XY:

33826

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30723

American (AMR)

AF:

0.00

AC:

AN:

10594

Ashkenazi Jewish (ASJ)

AF:

0.000378

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3521

South Asian (SAS)

AF:

0.00

AC:

AN:

2609

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6039

Middle Eastern (MID)

AF:

0.00922

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000358

AC:

AN:

53096

Other (OTH)

AF:

0.000661

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000462

Hom.:

Bravo

AF:

0.000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000288

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.96

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.19

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.81

M_CAP

Benign

0.0041

MetaRNN

Benign

0.064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.075

PhyloP100

0.52

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.8

REVEL

Benign

0.056

Sift

Benign

0.11

Sift4G

Benign

0.31

Polyphen

0.0010

Vest4

0.17

MVP

0.23

ClinPred

0.022

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.28

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over