X-66599555-C-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_021783.5(EDA2R):c.823G>T(p.Gly275Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,188,189 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 78 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G275E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00023 (0 hom. 73 hem.)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.491

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11104983).
• BP6: Variant X-66599555-C-A is Benign according to our data. Variant chrX-66599555-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2358184.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAd at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA2R	NM_021783.5	c.823G>T	p.Gly275Trp	missense_variant	6/7	ENST00000374719.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA2R	ENST00000374719.8	c.823G>T	p.Gly275Trp	missense_variant	6/7	1	NM_021783.5	P1
EDA2R	ENST00000253392.5	c.886G>T	p.Gly296Trp	missense_variant	6/6	1
EDA2R	ENST00000396050.5	c.886G>T	p.Gly296Trp	missense_variant	6/7	5
EDA2R	ENST00000451436.6	c.823G>T	p.Gly275Trp	missense_variant	6/7	5		P1

Frequencies

GnomAD3 genomes AF: 0.000135 AC: 15 AN: 111142 Hom.: 0 Cov.: 23 AF XY: 0.000150 AC XY: 5 AN XY: 33360

Gnomad AFR AF: 0.00

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: 0.000283

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000124 AC: 18 AN: 145361 Hom.: 0 AF XY: 0.0000920 AC XY: 4 AN XY: 43473

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000892

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000280

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000230 AC: 248 AN: 1077047 Hom.: 0 Cov.: 32 AF XY: 0.000209 AC XY: 73 AN XY: 349829

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000687

Gnomad4 SAS exome AF: 0.0000195

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000289

Gnomad4 OTH exome AF: 0.000110

GnomAD4 genome AF: 0.000135 AC: 15 AN: 111142 Hom.: 0 Cov.: 23 AF XY: 0.000150 AC XY: 5 AN XY: 33360

Gnomad4 AFR AF: 0.00

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: 0.000283

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000242 Hom.: 10

Bravo AF: 0.000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.0000753 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.886G>T (p.G296W) alteration is located in exon 6 (coding exon 6) of the EDA2R gene. This alteration results from a G to T substitution at nucleotide position 886, causing the glycine (G) at amino acid position 296 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

EDA2R: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	6.7
Dann	Benign	0.95
DEOGEN2	Benign	0.12	T;.;T;.
FATHMM_MKL	Benign	0.049	N
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.55	N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.76	N;.;.;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.022	D;.;.;D
Sift4G	Uncertain	0.057	T;T;T;T
Polyphen		0.66	P;P;P;P
Vest4		0.25
MVP		0.64
ClinPred		0.057	T
GERP RS		0.83
Varity_R		0.050
gMVP		0.16

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

Other links and lift over

dbSNP: rs201070562; hg19: chrX-65819397;