NM_021783.5:c.275G>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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 Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA2R	NM_021783.5	c.275G>T	p.Arg92Leu	missense_variant	Exon 4 of 7	ENST00000374719.8	NP_068555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA2R	ENST00000374719.8	c.275G>T	p.Arg92Leu	missense_variant	Exon 4 of 7	1	NM_021783.5	ENSP00000363851.3
EDA2R	ENST00000253392.5	c.275G>T	p.Arg92Leu	missense_variant	Exon 3 of 6	1		ENSP00000253392.5
EDA2R	ENST00000396050.5	c.275G>T	p.Arg92Leu	missense_variant	Exon 3 of 7	5		ENSP00000379365.2
EDA2R	ENST00000451436.6	c.275G>T	p.Arg92Leu	missense_variant	Exon 4 of 7	5		ENSP00000415242.3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;T;.
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.88	.;D;D;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;L;L
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.9	D;D;.;D
REVEL	Benign	0.089
Sift	Uncertain	0.022	D;D;.;D
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.093	B;P;B;P
Vest4		0.54
MutPred		0.57		Loss of methylation at K93 (P = 0.0522);Loss of methylation at K93 (P = 0.0522);Loss of methylation at K93 (P = 0.0522);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs200268345; hg19: chrX-65824340;