X-66602672-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021783.5(EDA2R):c.478C>T(p.Leu160Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000919 in 1,088,436 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 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)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0970

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2136155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA2R	NM_021783.5	c.478C>T	p.Leu160Phe	missense_variant	5/7	ENST00000374719.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA2R	ENST00000374719.8	c.478C>T	p.Leu160Phe	missense_variant	5/7	1	NM_021783.5	P1
EDA2R	ENST00000253392.5	c.478C>T	p.Leu160Phe	missense_variant	4/6	1
EDA2R	ENST00000396050.5	c.478C>T	p.Leu160Phe	missense_variant	4/7	5
EDA2R	ENST00000451436.6	c.478C>T	p.Leu160Phe	missense_variant	5/7	5		P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.19e-7 AC: 1 AN: 1088436 Hom.: 0 Cov.: 29 AF XY: 0.00000281 AC XY: 1 AN XY: 355906

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: 0.00

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

Mar 06, 2023

The c.478C>T (p.L160F) alteration is located in exon 4 (coding exon 4) of the EDA2R gene. This alteration results from a C to T substitution at nucleotide position 478, causing the leucine (L) at amino acid position 160 to be replaced by a phenylalanine (F). 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	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	14
Dann	Benign	0.97
DEOGEN2	Benign	0.11	T;.;T;.
FATHMM_MKL	Benign	0.37	N
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.63	N;N;N;N
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;N;.;N
REVEL	Benign	0.20
Sift	Benign	0.27	T;T;.;T
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.0050	B;B;B;B
Vest4		0.15
MutPred		0.24		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		0.81
ClinPred		0.093	T
GERP RS		0.26
Varity_R		0.19
gMVP		0.23

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-65822514; COSMIC: COSV105873730;