X-66599555-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_021783.5(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 NM_021783.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter 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 -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 GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA2R	NM_021783.5	c.823G>C	p.Gly275Arg	missense_variant	6/7	ENST00000374719.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA2R	ENST00000374719.8	c.823G>C	p.Gly275Arg	missense_variant	6/7	1	NM_021783.5	P1
EDA2R	ENST00000253392.5	c.886G>C	p.Gly296Arg	missense_variant	6/6	1
EDA2R	ENST00000396050.5	c.886G>C	p.Gly296Arg	missense_variant	6/7	5
EDA2R	ENST00000451436.6	c.823G>C	p.Gly275Arg	missense_variant	6/7	5		P1

Frequencies

GnomAD3 genomes AF: 0.0000540 AC: 6 AN: 111143 Hom.: 0 Cov.: 23 AF XY: 0.0000899 AC XY: 3 AN XY: 33361

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: 11 AN: 145361 Hom.: 0 AF XY: 0.0000230 AC XY: 1 AN XY: 43473

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: 22 AN: 1077047 Hom.: 0 Cov.: 32 AF XY: 0.0000200 AC XY: 7 AN XY: 349829

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: 6 AN: 111143 Hom.: 0 Cov.: 23 AF XY: 0.0000899 AC XY: 3 AN XY: 33361

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

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	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.11
Dann	Benign	0.35
DEOGEN2	Benign	0.066	T;.;T;.
FATHMM_MKL	Benign	0.038	N
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.049	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.14	N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.24	T
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	T
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

Other links and lift over

dbSNP: rs201070562; hg19: chrX-65819397;