chrX-66604498-C-A

Variant names:

• chrX-66604498-C-A
• rs200268345
• NM_021783.5:c.275G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021783.5(EDA2R):​c.275G>T​(p.Arg92Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,093,756 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R92Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.516
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• X-linked hypohidrotic ectodermal dysplasia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26390836).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021783.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA2R	NM_021783.5	MANE Select	c.275G>T	p.Arg92Leu	missense	Exon 4 of 7	NP_068555.2	Q9HAV5-1
	EDA2R	NM_001242310.1		c.275G>T	p.Arg92Leu	missense	Exon 3 of 7	NP_001229239.1	Q9HAV5
	EDA2R	NM_001324206.2		c.275G>T	p.Arg92Leu	missense	Exon 4 of 7	NP_001311135.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA2R	ENST00000374719.8	TSL:1 MANE Select	c.275G>T	p.Arg92Leu	missense	Exon 4 of 7	ENSP00000363851.3	Q9HAV5-1
	EDA2R	ENST00000253392.5	TSL:1	c.275G>T	p.Arg92Leu	missense	Exon 3 of 6	ENSP00000253392.5	Q9HAV5-2
	EDA2R	ENST00000396050.5	TSL:5	c.275G>T	p.Arg92Leu	missense	Exon 3 of 7	ENSP00000379365.2	Q9HAV5-2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1093756 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 359576

African (AFR) AF: 0.00 AC: 0 AN: 26326

American (AMR) AF: 0.00 AC: 0 AN: 35045

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19264

East Asian (EAS) AF: 0.00 AC: 0 AN: 30119

South Asian (SAS) AF: 0.00 AC: 0 AN: 53120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839459

Other (OTH) AF: 0.00 AC: 0 AN: 45894

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.52
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.089
Sift	Uncertain	0.022	D
Sift4G	Benign	0.11	T
Polyphen		0.093	B
Vest4		0.54
MutPred		0.57		Loss of methylation at K93 (P = 0.0522)
MVP		0.51
ClinPred		0.59	D
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.46
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200268345; hg19: chrX-65824340;