X-66599804-C-T

Position:

chrX-66599804-C-T

Variant summary

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

The ENST00000374719.8(EDA2R):c.574G>A(p.Val192Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,206,775 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 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 (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000025 ( 0 hom. 15 hem. )

Consequence

EDA2R
ENST00000374719.8 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.749

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=0.037461728).

BP6

Variant X-66599804-C-T is Benign according to our data. Variant chrX-66599804-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2474991.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA2R	NM_021783.5 linkuse as main transcript	c.574G>A	p.Val192Met	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.574G>A	p.Val192Met	missense_variant	6/7	1	NM_021783.5	ENSP00000363851	P1	Q9HAV5-1
EDA2R	ENST00000253392.5 linkuse as main transcript	c.637G>A	p.Val213Met	missense_variant	6/6	1		ENSP00000253392		Q9HAV5-2
EDA2R	ENST00000396050.5 linkuse as main transcript	c.637G>A	p.Val213Met	missense_variant	6/7	5		ENSP00000379365		Q9HAV5-2
EDA2R	ENST00000451436.6 linkuse as main transcript	c.574G>A	p.Val192Met	missense_variant	6/7	5		ENSP00000415242	P1	Q9HAV5-1

Frequencies

GnomAD3 genomes

AF:

0.00000897

AC:

AN:

111474

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33670

show subpopulations

Gnomad AFR

AF:

0.0000327

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000514

AC:

AN:

175084

Hom.:

AF XY:

0.0000823

AC XY:

AN XY:

60742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000137

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000226

Gnomad FIN exome

AF:

0.000129

Gnomad NFE exome

AF:

0.0000129

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1095301

Hom.:

Cov.:

AF XY:

0.0000416

AC XY:

AN XY:

360953

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000286

Gnomad4 ASJ exome

AF:

0.0000518

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000225

Gnomad4 FIN exome

AF:

0.0000743

Gnomad4 NFE exome

AF:

0.00000951

Gnomad4 OTH exome

AF:

0.0000435

GnomAD4 genome

AF:

0.00000897

AC:

AN:

111474

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33670

show subpopulations

Gnomad4 AFR

AF:

0.0000327

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000509

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

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

Jan 10, 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

0.069

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.0070

DANN

Benign

0.25

DEOGEN2

Benign

0.045

T;.;T;.

FATHMM_MKL

Benign

0.00088

LIST_S2

Benign

0.55

.;T;T;.

M_CAP

Benign

0.012

MetaRNN

Benign

0.037

T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

-0.90

N;.;N;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.14

N;.;.;N

REVEL

Benign

0.24

Sift

Benign

0.44

T;.;.;T

Sift4G

Benign

0.19

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.091

MutPred

0.10

Loss of sheet (P = 0.0457);.;Loss of sheet (P = 0.0457);.;

MVP

0.76

ClinPred

0.015

GERP RS

-6.9

Varity_R

0.039

gMVP

0.077

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