X-66604439-G-A

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.334C>T(p.Pro112Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00387 in 1,206,820 control chromosomes in the GnomAD database, including 11 homozygotes. There are 1,482 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., 66 hem., cov: 22)
  • Exomes 𝑓: 0.0040 (10 hom. 1416 hem.)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 5.18

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=0.007465422).
• BP6: Variant X-66604439-G-A is Benign according to our data. Variant chrX-66604439-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 718792.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-66604439-G-A is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAd at 66 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA2R	NM_021783.5	c.334C>T	p.Pro112Ser	missense_variant	4/7	ENST00000374719.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA2R	ENST00000374719.8	c.334C>T	p.Pro112Ser	missense_variant	4/7	1	NM_021783.5	P1
EDA2R	ENST00000253392.5	c.334C>T	p.Pro112Ser	missense_variant	3/6	1
EDA2R	ENST00000396050.5	c.334C>T	p.Pro112Ser	missense_variant	3/7	5
EDA2R	ENST00000451436.6	c.334C>T	p.Pro112Ser	missense_variant	4/7	5		P1

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 260 AN: 111498 Hom.: 1 Cov.: 22 AF XY: 0.00196 AC XY: 66 AN XY: 33678

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00113

Gnomad ASJ AF: 0.00493

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000384

Gnomad FIN AF: 0.000827

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00396

Gnomad OTH AF: 0.00135

GnomAD3 exomes AF: 0.00230 AC: 416 AN: 180972 Hom.: 3 AF XY: 0.00229 AC XY: 150 AN XY: 65624

Gnomad AFR exome AF: 0.000382

Gnomad AMR exome AF: 0.000557

Gnomad ASJ exome AF: 0.00420

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000108

Gnomad FIN exome AF: 0.000377

Gnomad NFE exome AF: 0.00432

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.00403 AC: 4414 AN: 1095268 Hom.: 10 Cov.: 29 AF XY: 0.00392 AC XY: 1416 AN XY: 361012

Gnomad4 AFR exome AF: 0.000380

Gnomad4 AMR exome AF: 0.000683

Gnomad4 ASJ exome AF: 0.00585

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000112

Gnomad4 FIN exome AF: 0.000717

Gnomad4 NFE exome AF: 0.00489

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00233 AC: 260 AN: 111552 Hom.: 1 Cov.: 22 AF XY: 0.00196 AC XY: 66 AN XY: 33742

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00113

Gnomad4 ASJ AF: 0.00493

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000385

Gnomad4 FIN AF: 0.000827

Gnomad4 NFE AF: 0.00396

Gnomad4 OTH AF: 0.00133

Alfa AF: 0.00360 Hom.: 20

Bravo AF: 0.00241

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00485 AC: 14

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00372 AC: 25

ExAC AF: 0.00246 AC: 299

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;D;.
FATHMM_MKL	Benign	0.69	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.0075	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;L;L
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.1	D;D;.;D
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.82	P;D;P;D
Vest4		0.32
MVP		0.19
ClinPred		0.13	T
GERP RS		3.4
Varity_R		0.63
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs12837393; hg19: chrX-65824281;