X-66599543-C-T

Position:

• chrX-66599543-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021783.5(EDA2R):​c.835G>A​(p.Val279Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.412

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054790556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA2R	NM_021783.5	c.835G>A	p.Val279Ile	missense_variant	6/7	ENST00000374719.8	NP_068555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA2R	ENST00000374719.8	c.835G>A	p.Val279Ile	missense_variant	6/7	1	NM_021783.5	ENSP00000363851.3
EDA2R	ENST00000253392.5	c.898G>A	p.Val300Ile	missense_variant	6/6	1		ENSP00000253392.5
EDA2R	ENST00000396050.5	c.898G>A	p.Val300Ile	missense_variant	6/7	5		ENSP00000379365.2
EDA2R	ENST00000451436.6	c.835G>A	p.Val279Ile	missense_variant	6/7	5		ENSP00000415242.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2024

The c.898G>A (p.V300I) alteration is located in exon 6 (coding exon 6) of the EDA2R gene. This alteration results from a G to A substitution at nucleotide position 898, causing the valine (V) at amino acid position 300 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.38
DANN	Benign	0.51
DEOGEN2	Benign	0.049	T;.;T;.
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.56	.;T;T;.
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.055	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N;.;N;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.14	N;.;.;N
REVEL	Benign	0.14
Sift	Benign	0.52	T;.;.;T
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.064
MutPred		0.11		Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);.;
MVP		0.49
ClinPred		0.019	T
GERP RS		-0.61
Varity_R		0.035
gMVP		0.084

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-65819385;