NM_021783.5:c.685C>T

Variant names:

• chrX-66599693-G-A
• rs1928171564
• NM_021783.5:c.685C>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.685C>T​(p.Pro229Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000897 in 111,506 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.428
• 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: 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=0.08546585).

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.685C>T	p.Pro229Ser	missense	Exon 6 of 7	NP_068555.2	Q9HAV5-1
	EDA2R	NM_001242310.1		c.748C>T	p.Pro250Ser	missense	Exon 6 of 7	NP_001229239.1	Q9HAV5
	EDA2R	NM_001324206.2		c.691C>T	p.Pro231Ser	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.685C>T	p.Pro229Ser	missense	Exon 6 of 7	ENSP00000363851.3	Q9HAV5-1
	EDA2R	ENST00000253392.5	TSL:1	c.748C>T	p.Pro250Ser	missense	Exon 6 of 6	ENSP00000253392.5	Q9HAV5-2
	EDA2R	ENST00000396050.5	TSL:5	c.748C>T	p.Pro250Ser	missense	Exon 6 of 7	ENSP00000379365.2	Q9HAV5-2

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111506 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000283

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111506 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33694

African (AFR) AF: 0.00 AC: 0 AN: 30661

American (AMR) AF: 0.00 AC: 0 AN: 10521

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.000283 AC: 1 AN: 3532

South Asian (SAS) AF: 0.00 AC: 0 AN: 2657

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6055

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53032

Other (OTH) AF: 0.00 AC: 0 AN: 1485

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	0.094
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.085	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.43
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.28	T
Polyphen		0.19	B
Vest4		0.074
MutPred		0.19		Gain of sheet (P = 0.0266)
MVP		0.79
ClinPred		0.45	T
GERP RS		2.7
Varity_R		0.23
gMVP		0.18
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1928171564; hg19: chrX-65819535;