rs876657641

Variant names:

• chrX-70033470-G-A
• rs876657641
• NM_001399.5:c.866G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-70033470-G-A
• chrX-70033470-G-C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 15P and 4B. PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong BS2

The NM_001399.5(EDA):​c.866G>A​(p.Arg289His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,098,037 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R289P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 5 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.36
• Publications: 9 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001399.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-70033469-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 253054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 X-linked hypohidrotic ectodermal dysplasia, tooth agenesis, selective, X-linked, 1, tooth agenesis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant X-70033470-G-A is Pathogenic according to our data. Variant chrX-70033470-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 228257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 11 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.866G>A	p.Arg289His	missense	Exon 7 of 8	NP_001390.1	Q92838-1
	EDA	NM_001005609.2		c.866G>A	p.Arg289His	missense	Exon 7 of 8	NP_001005609.1	Q92838-3
	EDA	NM_001440761.1		c.857G>A	p.Arg286His	missense	Exon 7 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.866G>A	p.Arg289His	missense	Exon 7 of 8	ENSP00000363680.4	Q92838-1
	EDA	ENST00000374553.6	TSL:1	c.866G>A	p.Arg289His	missense	Exon 7 of 8	ENSP00000363681.2	Q92838-3
	EDA	ENST00000524573.5	TSL:1	c.857G>A	p.Arg286His	missense	Exon 7 of 8	ENSP00000432585.1	Q92838-9

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1098037 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 363395

African (AFR) AF: 0.00 AC: 0 AN: 26399

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000131 AC: 11 AN: 841952

Other (OTH) AF: 0.00 AC: 0 AN: 46086

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hypohidrotic X-linked ectodermal dysplasia (2)
1	-	-	Anhidrotic ectodermal dysplasia (1)
1	-	-	Ectodermal dysplasia (1)
1	-	-	Hypodontia (1)
1	-	-	Hypohidrotic X-linked ectodermal dysplasia;C1970757:Tooth agenesis, selective, X-linked, 1 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.5	L
PhyloP100		9.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.83	N
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.63		Loss of methylation at R289 (P = 0.0444)
MVP		0.99
MPC		1.2
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.91
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs876657641; hg19: chrX-69253320; COSMIC: COSV100999888; COSMIC: COSV100999888;