NM_001399.5:c.467G>A

Variant names:

• chrX-69957097-G-A
• rs132630314
• NM_001399.5:c.467G>A

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001399.5(EDA):​c.467G>A​(p.Arg156His) variant causes a missense change. The variant allele was found at a frequency of 0.00000165 in 1,209,437 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000060828: Furthermore, functional studies have shown that the change to Histidine (His) at position 156 affects protein cleavage (Chen 2001, Elomaa 2001)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.55
• Publications: 28 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 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000060828: Furthermore, functional studies have shown that the change to Histidine (His) at position 156 affects protein cleavage (Chen 2001, Elomaa 2001).; SCV000630027: Experimental studies have shown that this missense change affects EDA function (PMID: 11416205).; SCV006581741: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11416205, 21357618)."; SCV000321580: Published functional studies demonstrate a damaging effect due to a drastic reduction in the cleavage of ectodysplasin-A as compared to wild-type, preventing the generation of a soluble ectodysplasin-A ligand (Chen et al., 2001); PMID: 26273176, 23744313, 26411740, 11416205, 27305980, 26345974, 18231121, 11295832, 11309369, 18076698, 9683615, 11279189, 11378824, 28981473, 21357618, 34426522, 32690319, 32176048, 31924237, 29220840, 31796081, 34863015, 25333067, 17686277, 26502894, 18666859
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 3 uncertain in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-69957096-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11036.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, 0.956
• PP5: Variant X-69957097-G-A is Pathogenic according to our data. Variant chrX-69957097-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.467G>A	p.Arg156His	missense	Exon 2 of 8	NP_001390.1	Q92838-1
	EDA	NM_001005609.2		c.467G>A	p.Arg156His	missense	Exon 2 of 8	NP_001005609.1	Q92838-3
	EDA	NM_001440761.1		c.467G>A	p.Arg156His	missense	Exon 2 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.467G>A	p.Arg156His	missense	Exon 2 of 8	ENSP00000363680.4	Q92838-1
	EDA	ENST00000374553.6	TSL:1	c.467G>A	p.Arg156His	missense	Exon 2 of 8	ENSP00000363681.2	Q92838-3
	EDA	ENST00000524573.5	TSL:1	c.467G>A	p.Arg156His	missense	Exon 2 of 8	ENSP00000432585.1	Q92838-9

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112401 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1097036 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362430

African (AFR) AF: 0.00 AC: 0 AN: 26379

American (AMR) AF: 0.00 AC: 0 AN: 35178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19369

East Asian (EAS) AF: 0.00 AC: 0 AN: 30149

South Asian (SAS) AF: 0.00 AC: 0 AN: 54023

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40501

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841267

Other (OTH) AF: 0.00 AC: 0 AN: 46037

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112401 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34579

African (AFR) AF: 0.00 AC: 0 AN: 30952

American (AMR) AF: 0.00 AC: 0 AN: 10665

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2661

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2727

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6131

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53286

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.0000198 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Hypohidrotic X-linked ectodermal dysplasia (4)
1	-	-	Ectodermal dysplasia (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	0.53
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	0.90	L
PhyloP100		5.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.011	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.52
MutPred		0.87		Loss of MoRF binding (P = 0.0444)
MVP		1.0
MPC		0.97
ClinPred		0.82	D
GERP RS		5.0
PromoterAI		-0.023	Neutral
Varity_R		0.67
gMVP		0.82
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs132630314; hg19: chrX-69176947; COSMIC: COSV108911378;