chrX-69616514-G-T

Variant names:

• chrX-69616514-G-T
• rs132630309
• NM_001399.5:c.206G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BS1_Supporting BS2

The NM_001399.5(EDA):​c.206G>T​(p.Arg69Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00485 in 1,210,205 control chromosomes in the GnomAD database, including 17 homozygotes. There are 1,824 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69W) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., 89 hem., cov: 24)
  • Exomes 𝑓: 0.0050 (16 hom. 1735 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:13
• Conservation: PhyloP100: 1.86
• Publications: 10 publications found

Genes affected

EDA (HGNC:3157): (ectodysplasin A) The protein encoded by this gene is a type II membrane protein that can be cleaved by furin to produce a secreted form. The encoded protein, which belongs to the tumor necrosis factor family, acts as a homotrimer and may be involved in cell-cell signaling during the development of ectodermal organs. Defects in this gene are a cause of ectodermal dysplasia, anhidrotic, which is also known as X-linked hypohidrotic ectodermal dysplasia. Several transcript variants encoding many different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EDA Gene-Disease associations (from GenCC):

• tooth agenesis, selective, X-linked, 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• X-linked hypohidrotic ectodermal dysplasia

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 2 uncertain in NM_001399.5
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 1.7843 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to tooth agenesis, selective, X-linked, 1, X-linked hypohidrotic ectodermal dysplasia, tooth agenesis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.023254514).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00301 (338/112334) while in subpopulation NFE AF = 0.00538 (285/53015). AF 95% confidence interval is 0.00486. There are 1 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 338 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001399.5. 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
	EDA	NM_001399.5	MANE Select	c.206G>T	p.Arg69Leu	missense	Exon 1 of 8	NP_001390.1	Q92838-1
	EDA	NM_001005609.2		c.206G>T	p.Arg69Leu	missense	Exon 1 of 8	NP_001005609.1	Q92838-3
	EDA	NM_001440761.1		c.206G>T	p.Arg69Leu	missense	Exon 1 of 8	NP_001427690.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA	ENST00000374552.9	TSL:1 MANE Select	c.206G>T	p.Arg69Leu	missense	Exon 1 of 8	ENSP00000363680.4	Q92838-1
	EDA	ENST00000374553.6	TSL:1	c.206G>T	p.Arg69Leu	missense	Exon 1 of 8	ENSP00000363681.2	Q92838-3
	EDA	ENST00000524573.5	TSL:1	c.206G>T	p.Arg69Leu	missense	Exon 1 of 8	ENSP00000432585.1	Q92838-9

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 339 AN: 112284 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00185

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.000285

Gnomad SAS AF: 0.00189

Gnomad FIN AF: 0.000320

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00537

Gnomad OTH AF: 0.00264

GnomAD2 exomes AF: 0.00286 AC: 519 AN: 181348 AF XY: 0.00302

Gnomad AFR exome AF: 0.000997

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.00255

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000694

Gnomad NFE exome AF: 0.00517

Gnomad OTH exome AF: 0.00267

GnomAD4 exome AF: 0.00504 AC: 5529 AN: 1097871 Hom.: 16 Cov.: 32 AF XY: 0.00477 AC XY: 1735 AN XY: 363367

African (AFR) AF: 0.00110 AC: 29 AN: 26398

American (AMR) AF: 0.000852 AC: 30 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 54 AN: 19365

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.00159 AC: 86 AN: 54135

European-Finnish (FIN) AF: 0.000892 AC: 36 AN: 40364

Middle Eastern (MID) AF: 0.00290 AC: 12 AN: 4134

European-Non Finnish (NFE) AF: 0.00607 AC: 5112 AN: 842008

Other (OTH) AF: 0.00369 AC: 170 AN: 46074

GnomAD4 genome AF: 0.00301 AC: 338 AN: 112334 Hom.: 1 Cov.: 24 AF XY: 0.00258 AC XY: 89 AN XY: 34500

African (AFR) AF: 0.000580 AC: 18 AN: 31026

American (AMR) AF: 0.00176 AC: 19 AN: 10822

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 4 AN: 2651

East Asian (EAS) AF: 0.000286 AC: 1 AN: 3498

South Asian (SAS) AF: 0.00189 AC: 5 AN: 2645

European-Finnish (FIN) AF: 0.000320 AC: 2 AN: 6244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00538 AC: 285 AN: 53015

Other (OTH) AF: 0.00261 AC: 4 AN: 1535

Alfa AF: 0.00365 Hom.: 23

Bravo AF: 0.00296

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00450 AC: 13

ESP6500AA AF: 0.00130 AC: 5

ESP6500EA AF: 0.00550 AC: 37

ExAC AF: 0.00321 AC: 390

EpiCase AF: 0.00502

EpiControl AF: 0.00439

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
2	2	2	Hypohidrotic X-linked ectodermal dysplasia (6)
-	-	3	not specified (3)
-	-	1	EDA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.023	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	0.81	L
PhyloP100		1.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.72
Sift	Benign	0.084	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.16
MVP		1.0
MPC		0.97
ClinPred		0.050	T
GERP RS		3.2
PromoterAI		0.052	Neutral
Varity_R		0.54
gMVP		0.71
Mutation Taster		=59/41	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs132630309; hg19: chrX-68836358; COSMIC: COSV58877505; COSMIC: COSV58877505;