X-66599555-C-G

Position:

chrX-66599555-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The ENST00000374719.8(EDA2R):c.823G>C(p.Gly275Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,188,190 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G275W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000020 ( 0 hom. 7 hem. )

Consequence

EDA2R
ENST00000374719.8 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B: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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04923317).

BP6

Variant X-66599555-C-G is Benign according to our data. Variant chrX-66599555-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3087119.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA2R	NM_021783.5 linkuse as main transcript	c.823G>C	p.Gly275Arg	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>C	p.Gly275Arg	missense_variant	6/7	1	NM_021783.5	ENSP00000363851	P1	Q9HAV5-1
EDA2R	ENST00000253392.5 linkuse as main transcript	c.886G>C	p.Gly296Arg	missense_variant	6/6	1		ENSP00000253392		Q9HAV5-2
EDA2R	ENST00000396050.5 linkuse as main transcript	c.886G>C	p.Gly296Arg	missense_variant	6/7	5		ENSP00000379365		Q9HAV5-2
EDA2R	ENST00000451436.6 linkuse as main transcript	c.823G>C	p.Gly275Arg	missense_variant	6/7	5		ENSP00000415242	P1	Q9HAV5-1

Frequencies

GnomAD3 genomes

AF:

0.0000540

AC:

AN:

111143

Hom.:

Cov.:

AF XY:

0.0000899

AC XY:

AN XY:

33361

show subpopulations

Gnomad AFR

AF:

0.0000656

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000287

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000168

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000757

AC:

AN:

145361

Hom.:

AF XY:

0.0000230

AC XY:

AN XY:

43473

show subpopulations

Gnomad AFR exome

AF:

0.0000954

Gnomad AMR exome

AF:

0.000169

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000892

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000376

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000204

AC:

AN:

1077047

Hom.:

Cov.:

AF XY:

0.0000200

AC XY:

AN XY:

349829

show subpopulations

Gnomad4 AFR exome

AF:

0.000154

Gnomad4 AMR exome

AF:

0.000155

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000344

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000153

Gnomad4 NFE exome

AF:

0.00000241

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000540

AC:

AN:

111143

Hom.:

Cov.:

AF XY:

0.0000899

AC XY:

AN XY:

33361

show subpopulations

Gnomad4 AFR

AF:

0.0000656

Gnomad4 AMR

AF:

0.000287

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000168

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.11

DANN

Benign

0.35

DEOGEN2

Benign

0.066

T;.;T;.

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.60

.;T;T;.

M_CAP

Benign

0.037

MetaRNN

Benign

0.049

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.14

N;.;N;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

0.36

N;.;.;N

REVEL

Benign

0.21

Sift

Benign

0.47

T;.;.;T

Sift4G

Benign

0.91

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.064

MutPred

0.15

Gain of methylation at G275 (P = 0.0463);.;Gain of methylation at G275 (P = 0.0463);.;

MVP

0.73

ClinPred

0.0052

GERP RS

0.83

Varity_R

0.036

gMVP

0.14

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