X-66605144-C-T

Variant names:

• chrX-66605144-C-T
• rs1385699
• NM_021783.5:c.170G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021783.5(EDA2R):​c.170G>A​(p.Arg57Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 110,140 control chromosomes in the GnomAD database, including 18,717 homozygotes. There are 20,498 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.62 (18717 hom., 20498 hem., cov: 22)
  • Exomes 𝑓: 0.80 (238560 hom. 291378 hem.)
  • Failed GnomAD Quality Control
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.36
• Publications: 47 publications found

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]

EDA2R Gene-Disease associations (from GenCC):

• X-linked hypohidrotic ectodermal dysplasia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.7450592E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA2R	NM_021783.5	c.170G>A	p.Arg57Lys	missense_variant	Exon 3 of 7	ENST00000374719.8	NP_068555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA2R	ENST00000374719.8	c.170G>A	p.Arg57Lys	missense_variant	Exon 3 of 7	1	NM_021783.5	ENSP00000363851.3
EDA2R	ENST00000253392.5	c.170G>A	p.Arg57Lys	missense_variant	Exon 2 of 6	1		ENSP00000253392.5
EDA2R	ENST00000396050.5	c.170G>A	p.Arg57Lys	missense_variant	Exon 2 of 7	5		ENSP00000379365.2
EDA2R	ENST00000451436.6	c.170G>A	p.Arg57Lys	missense_variant	Exon 3 of 7	5		ENSP00000415242.3

Frequencies

GnomAD3 genomes AF: 0.624 AC: 68690 AN: 110084 Hom.: 18725 Cov.: 22

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.867

Gnomad AMR AF: 0.821

Gnomad ASJ AF: 0.920

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.902

Gnomad FIN AF: 0.762

Gnomad MID AF: 0.733

Gnomad NFE AF: 0.797

Gnomad OTH AF: 0.695

GnomAD2 exomes AF: 0.793 AC: 140733 AN: 177363 AF XY: 0.813

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.903

Gnomad ASJ exome AF: 0.906

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.758

Gnomad NFE exome AF: 0.802

Gnomad OTH exome AF: 0.831

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.800 AC: 876361 AN: 1096124 Hom.: 238560 Cov.: 42 AF XY: 0.805 AC XY: 291378 AN XY: 361838

African (AFR) AF: 0.114 AC: 3007 AN: 26370

American (AMR) AF: 0.893 AC: 31289 AN: 35025

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 17616 AN: 19350

East Asian (EAS) AF: 0.999 AC: 30075 AN: 30093

South Asian (SAS) AF: 0.889 AC: 47876 AN: 53845

European-Finnish (FIN) AF: 0.760 AC: 30687 AN: 40369

Middle Eastern (MID) AF: 0.763 AC: 3154 AN: 4132

European-Non Finnish (NFE) AF: 0.804 AC: 676443 AN: 840934

Other (OTH) AF: 0.787 AC: 36214 AN: 46006

GnomAD4 genome AF: 0.624 AC: 68684 AN: 110140 Hom.: 18717 Cov.: 22 AF XY: 0.633 AC XY: 20498 AN XY: 32386

African (AFR) AF: 0.131 AC: 4007 AN: 30523

American (AMR) AF: 0.821 AC: 8448 AN: 10286

Ashkenazi Jewish (ASJ) AF: 0.920 AC: 2408 AN: 2618

East Asian (EAS) AF: 0.998 AC: 3467 AN: 3474

South Asian (SAS) AF: 0.902 AC: 2248 AN: 2493

European-Finnish (FIN) AF: 0.762 AC: 4348 AN: 5708

Middle Eastern (MID) AF: 0.730 AC: 157 AN: 215

European-Non Finnish (NFE) AF: 0.797 AC: 41972 AN: 52655

Other (OTH) AF: 0.699 AC: 1044 AN: 1493

Alfa AF: 0.749 Hom.: 145454

Bravo AF: 0.613

TwinsUK AF: 0.797 AC: 2955

ALSPAC AF: 0.820 AC: 2370

ESP6500AA AF: 0.143 AC: 547

ESP6500EA AF: 0.798 AC: 5367

ExAC AF: 0.775 AC: 93954

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.18	T;.;T;.
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.55	.;T;T;.
MetaRNN	Benign	0.0000027	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.75	N;N;N;N
PhyloP100		2.4
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.90	N;N;.;N
REVEL	Benign	0.056
Sift	Benign	1.0	T;T;.;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.43	B;B;B;B
Vest4		0.11
ClinPred		0.0092	T
GERP RS		4.0
Varity_R		0.29
gMVP		0.47
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1385699; hg19: chrX-65824986; COSMIC: COSV107271298;