X-66604498-C-T

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.275G>A(p.Arg92Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,205,394 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 72 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 7 hem., cov: 22)
  • Exomes 𝑓: 0.00018 (0 hom. 65 hem.)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.516

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=0.06443906).
• BP6: Variant X-66604498-C-T is Benign according to our data. Variant chrX-66604498-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2266329.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA2R	NM_021783.5	c.275G>A	p.Arg92Gln	missense_variant	4/7	ENST00000374719.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA2R	ENST00000374719.8	c.275G>A	p.Arg92Gln	missense_variant	4/7	1	NM_021783.5	P1
EDA2R	ENST00000253392.5	c.275G>A	p.Arg92Gln	missense_variant	3/6	1
EDA2R	ENST00000396050.5	c.275G>A	p.Arg92Gln	missense_variant	3/7	5
EDA2R	ENST00000451436.6	c.275G>A	p.Arg92Gln	missense_variant	4/7	5		P1

Frequencies

GnomAD3 genomes AF: 0.000206 AC: 23 AN: 111590 Hom.: 0 Cov.: 22 AF XY: 0.000207 AC XY: 7 AN XY: 33766

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00844

Gnomad NFE AF: 0.000358

Gnomad OTH AF: 0.000669

GnomAD3 exomes AF: 0.000255 AC: 46 AN: 180480 Hom.: 0 AF XY: 0.000292 AC XY: 19 AN XY: 65162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000373

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.000907

GnomAD4 exome AF: 0.000183 AC: 200 AN: 1093754 Hom.: 0 Cov.: 29 AF XY: 0.000181 AC XY: 65 AN XY: 359576

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000285

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000188

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.000283

GnomAD4 genome AF: 0.000206 AC: 23 AN: 111640 Hom.: 0 Cov.: 22 AF XY: 0.000207 AC XY: 7 AN XY: 33826

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000378

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000358

Gnomad4 OTH AF: 0.000661

Alfa AF: 0.000497 Hom.: 23

Bravo AF: 0.000227

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000288 AC: 35

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

Jan 26, 2022

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	0.067
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.96
Cadd	Benign	12
Dann	Benign	0.97
DEOGEN2	Benign	0.19	T;.;T;.
FATHMM_MKL	Benign	0.36	N
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.064	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.075	N;N;N;N
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N;N;.;N
REVEL	Benign	0.056
Sift	Benign	0.11	T;T;.;T
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.17
MVP		0.23
ClinPred		0.022	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs200268345; hg19: chrX-65824340; COSMIC: COSV53632105;