chrX-66604439-G-A

Variant names:

• chrX-66604439-G-A
• rs12837393
• NM_021783.5:c.334C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.18
• Publications: 7 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 -16 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 VariationId is 718792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 66 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021783.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA2R	NM_021783.5	MANE Select	c.334C>T	p.Pro112Ser	missense	Exon 4 of 7	NP_068555.2	Q9HAV5-1
	EDA2R	NM_001242310.1		c.334C>T	p.Pro112Ser	missense	Exon 3 of 7	NP_001229239.1	Q9HAV5
	EDA2R	NM_001324206.2		c.334C>T	p.Pro112Ser	missense	Exon 4 of 7	NP_001311135.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA2R	ENST00000374719.8	TSL:1 MANE Select	c.334C>T	p.Pro112Ser	missense	Exon 4 of 7	ENSP00000363851.3	Q9HAV5-1
	EDA2R	ENST00000253392.5	TSL:1	c.334C>T	p.Pro112Ser	missense	Exon 3 of 6	ENSP00000253392.5	Q9HAV5-2
	EDA2R	ENST00000396050.5	TSL:5	c.334C>T	p.Pro112Ser	missense	Exon 3 of 7	ENSP00000379365.2	Q9HAV5-2

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 260 AN: 111498 Hom.: 1 Cov.: 22

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

GnomAD2 exomes AF: 0.00230 AC: 416 AN: 180972 AF XY: 0.00229

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 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

African (AFR) AF: 0.000380 AC: 10 AN: 26348

American (AMR) AF: 0.000683 AC: 24 AN: 35117

Ashkenazi Jewish (ASJ) AF: 0.00585 AC: 113 AN: 19305

East Asian (EAS) AF: 0.00 AC: 0 AN: 30153

South Asian (SAS) AF: 0.000112 AC: 6 AN: 53457

European-Finnish (FIN) AF: 0.000717 AC: 29 AN: 40445

Middle Eastern (MID) AF: 0.000971 AC: 4 AN: 4118

European-Non Finnish (NFE) AF: 0.00489 AC: 4113 AN: 840364

Other (OTH) AF: 0.00250 AC: 115 AN: 45961

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

African (AFR) AF: 0.000554 AC: 17 AN: 30666

American (AMR) AF: 0.00113 AC: 12 AN: 10600

Ashkenazi Jewish (ASJ) AF: 0.00493 AC: 13 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3520

South Asian (SAS) AF: 0.000385 AC: 1 AN: 2596

European-Finnish (FIN) AF: 0.000827 AC: 5 AN: 6047

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00396 AC: 210 AN: 53082

Other (OTH) AF: 0.00133 AC: 2 AN: 1505

Alfa AF: 0.00359 Hom.: 46

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.82	P
Vest4		0.32
MVP		0.19
ClinPred		0.13	T
GERP RS		3.4
Varity_R		0.63
gMVP		0.65
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12837393; hg19: chrX-65824281;