chrX-66605144-C-A

Variant names:

• chrX-66605144-C-A
• rs1385699
• NM_021783.5:c.170G>T

Variant summary

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

The NM_021783.5(EDA2R):​c.170G>T​(p.Arg57Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.36
• Publications: 47 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA2R	NM_021783.5	c.170G>T	p.Arg57Ile	missense_variant	Exon 3 of 7	ENST00000374719.8	NP_068555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA2R	ENST00000374719.8	c.170G>T	p.Arg57Ile	missense_variant	Exon 3 of 7	1	NM_021783.5	ENSP00000363851.3
EDA2R	ENST00000253392.5	c.170G>T	p.Arg57Ile	missense_variant	Exon 2 of 6	1		ENSP00000253392.5
EDA2R	ENST00000396050.5	c.170G>T	p.Arg57Ile	missense_variant	Exon 2 of 7	5		ENSP00000379365.2
EDA2R	ENST00000451436.6	c.170G>T	p.Arg57Ile	missense_variant	Exon 3 of 7	5		ENSP00000415242.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T;.;T;.
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	.;D;D;.
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	2.0	M;M;M;M
PhyloP100		2.4
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D;D;.;D
REVEL	Benign	0.082
Sift	Benign	0.11	T;T;.;T
Sift4G	Benign	0.070	T;T;T;T
Polyphen		0.99	D;P;D;P
Vest4		0.46
MutPred		0.49		Loss of catalytic residue at R57 (P = 0.0242);Loss of catalytic residue at R57 (P = 0.0242);Loss of catalytic residue at R57 (P = 0.0242);Loss of catalytic residue at R57 (P = 0.0242);
MVP		0.79
ClinPred		0.93	D
GERP RS		4.0
Varity_R		0.38
gMVP		0.55
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1385699; hg19: chrX-65824986;