X-66599804-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_021783.5(EDA2R):c.574G>A(p.Val192Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,206,775 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000025 (0 hom. 15 hem.)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.749

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037461728).
• BP6: Variant X-66599804-C-T is Benign according to our data. Variant chrX-66599804-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2474991.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA2R	NM_021783.5	c.574G>A	p.Val192Met	missense_variant	6/7	ENST00000374719.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA2R	ENST00000374719.8	c.574G>A	p.Val192Met	missense_variant	6/7	1	NM_021783.5	P1
EDA2R	ENST00000253392.5	c.637G>A	p.Val213Met	missense_variant	6/6	1
EDA2R	ENST00000396050.5	c.637G>A	p.Val213Met	missense_variant	6/7	5
EDA2R	ENST00000451436.6	c.574G>A	p.Val192Met	missense_variant	6/7	5		P1

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111474 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33670

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD3 exomes AF: 0.0000514 AC: 9 AN: 175084 Hom.: 0 AF XY: 0.0000823 AC XY: 5 AN XY: 60742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000137

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000226

Gnomad FIN exome AF: 0.000129

Gnomad NFE exome AF: 0.0000129

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.0000247 AC: 27 AN: 1095301 Hom.: 0 Cov.: 32 AF XY: 0.0000416 AC XY: 15 AN XY: 360953

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000286

Gnomad4 ASJ exome AF: 0.0000518

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000225

Gnomad4 FIN exome AF: 0.0000743

Gnomad4 NFE exome AF: 0.00000951

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111474 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33670

Gnomad4 AFR AF: 0.0000327

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000509 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.0070
Dann	Benign	0.25
DEOGEN2	Benign	0.045	T;.;T;.
FATHMM_MKL	Benign	0.00088	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.037	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.90	N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.14	N;.;.;N
REVEL	Benign	0.24
Sift	Benign	0.44	T;.;.;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.091
MutPred		0.10		Loss of sheet (P = 0.0457);.;Loss of sheet (P = 0.0457);.;
MVP		0.76
ClinPred		0.015	T
GERP RS		-6.9
Varity_R		0.039
gMVP		0.077

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

LitVar

Other links and lift over

dbSNP: rs778940212; hg19: chrX-65819646; COSMIC: COSV104388191;