X-66599665-G-T

Variant names:

• chrX-66599665-G-T
• rs766654958
• NM_021783.5:c.713C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_021783.5(EDA2R):​c.713C>A​(p.Ser238Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,095,102 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000016 (0 hom. 12 hem.)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.61
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27753478).
• BS2: High Hemizygotes in GnomAdExome4 at 12 XL gene

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.713C>A	p.Ser238Tyr	missense	Exon 6 of 7	NP_068555.2	Q9HAV5-1
	EDA2R	NM_001242310.1		c.776C>A	p.Ser259Tyr	missense	Exon 6 of 7	NP_001229239.1	Q9HAV5
	EDA2R	NM_001324206.2		c.719C>A	p.Ser240Tyr	missense	Exon 6 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.713C>A	p.Ser238Tyr	missense	Exon 6 of 7	ENSP00000363851.3	Q9HAV5-1
	EDA2R	ENST00000253392.5	TSL:1	c.776C>A	p.Ser259Tyr	missense	Exon 6 of 6	ENSP00000253392.5	Q9HAV5-2
	EDA2R	ENST00000396050.5	TSL:5	c.776C>A	p.Ser259Tyr	missense	Exon 6 of 7	ENSP00000379365.2	Q9HAV5-2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000403 AC: 7 AN: 173569 AF XY: 0.0000675

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 18 AN: 1095102 Hom.: 0 Cov.: 32 AF XY: 0.0000333 AC XY: 12 AN XY: 360886

African (AFR) AF: 0.00 AC: 0 AN: 26372

American (AMR) AF: 0.00 AC: 0 AN: 34963

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19321

East Asian (EAS) AF: 0.00 AC: 0 AN: 30040

South Asian (SAS) AF: 0.000338 AC: 18 AN: 53302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40277

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840727

Other (OTH) AF: 0.00 AC: 0 AN: 45979

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	2.0	M
PhyloP100		3.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.22		Loss of sheet (P = 0.0084)
MVP		0.94
ClinPred		0.34	T
GERP RS		2.7
Varity_R		0.31
gMVP		0.46
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs766654958; hg19: chrX-65819507;