Genetic Variant EDA2R:p.Thr129Ser (chrX-66602765-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021783.5(EDA2R):c.385A>T(p.Thr129Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000921 in 1,085,354 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

EDA2R
NM_021783.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0420

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04124978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA2R	NM_021783.5 link	c.385A>T	p.Thr129Ser	missense_variant	Exon 5 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.385A>T	p.Thr129Ser	missense_variant	Exon 5 of 7	1	NM_021783.5	ENSP00000363851.3	Q9HAV5-1
EDA2R	ENST00000253392.5 link	c.385A>T	p.Thr129Ser	missense_variant	Exon 4 of 6	1		ENSP00000253392.5	Q9HAV5-2
EDA2R	ENST00000396050.5 link	c.385A>T	p.Thr129Ser	missense_variant	Exon 4 of 7	5		ENSP00000379365.2	Q9HAV5-2
EDA2R	ENST00000451436.6 link	c.385A>T	p.Thr129Ser	missense_variant	Exon 5 of 7	5		ENSP00000415242.3	Q9HAV5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.21e-7

AC:

AN:

1085354

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

354574

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26147

American (AMR)

AF:

0.00

AC:

AN:

33589

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19009

East Asian (EAS)

AF:

0.00

AC:

AN:

29617

South Asian (SAS)

AF:

0.00

AC:

AN:

52024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39767

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4048

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

835567

Other (OTH)

AF:

0.00

AC:

AN:

45586

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.0

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.034

T;.;T;.

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.20

.;T;T;.

M_CAP

Benign

0.012

MetaRNN

Benign

0.041

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.81

N;N;N;N

PhyloP100

0.042

PrimateAI

Benign

0.35

PROVEAN

Benign

0.86

N;N;.;N

REVEL

Benign

0.15

Sift

Benign

0.77

T;T;.;T

Sift4G

Benign

0.98

T;T;T;T

Polyphen

0.0010

B;B;B;B

Vest4

0.049

MutPred

0.25

Gain of disorder (P = 0.0619);Gain of disorder (P = 0.0619);Gain of disorder (P = 0.0619);Gain of disorder (P = 0.0619);

MVP

0.79

ClinPred

0.023

GERP RS

3.5

Varity_R

0.053

gMVP

0.19

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over