X-66605082-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021783.5(EDA2R):c.232A>C(p.Thr78Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000457 in 1,094,626 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 0 hem.)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA2R	NM_021783.5	c.232A>C	p.Thr78Pro	missense_variant	3/7	ENST00000374719.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA2R	ENST00000374719.8	c.232A>C	p.Thr78Pro	missense_variant	3/7	1	NM_021783.5	P1
EDA2R	ENST00000253392.5	c.232A>C	p.Thr78Pro	missense_variant	2/6	1
EDA2R	ENST00000396050.5	c.232A>C	p.Thr78Pro	missense_variant	2/7	5
EDA2R	ENST00000451436.6	c.232A>C	p.Thr78Pro	missense_variant	3/7	5		P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000457 AC: 5 AN: 1094626 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 360452

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: 0.0000870

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

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

Aug 21, 2023

The c.232A>C (p.T78P) alteration is located in exon 2 (coding exon 2) of the EDA2R gene. This alteration results from a A to C substitution at nucleotide position 232, causing the threonine (T) at amino acid position 78 to be replaced by a proline (P). 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	Uncertain	0.43
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;D;.
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.5	M;M;M;M
MutationTaster	Benign	0.98	D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.0	D;D;.;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0060	D;D;.;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.45
MutPred		0.76		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.52
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.96
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1929413423; hg19: chrX-65824924;