chrX-69616310-T-C

Variant names:

• chrX-69616310-T-C
• rs397516659
• NM_001399.5:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001399.5(EDA):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: EDA NM_001399.5 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.56
• Publications: 6 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, Orphanet, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 50 pathogenic variants. Next in-frame start position is after 133 codons. Genomic position: 69957027. Lost 0.338 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-69616310-T-C is Pathogenic according to our data. Variant chrX-69616310-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 44190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.2T>C	p.Met1?	start_lost	Exon 1 of 8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.2T>C	p.Met1?	start_lost	Exon 1 of 8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Sep 20, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Met1Thr variant in EDA has been reported in at least 2 individuals with X-li nked hypohidrotic ectodermal dysplasia (XLHED). In addition, other variants dis rupting the start codon (Met) have been reported in individuals with XLHED (Met1 Lys, Met1Arg, Met1Leu; Cluzeau 2011, van der Hout 2008, Vincent 2001, Zhao 2008) . These variants are predicted to result in the loss of translation initiation and therefore, a loss of protein production. In summary, this variant is highly likely to be pathogenic. The presence of a hemizygous pathogenic variant in EDA is consistent with a diagnosis of X-Linked Hypohidrotic Ectodermal Dysplasia, b ut this information should be reconciled with the complete clinical history of t his individual. -

Hypohidrotic X-linked ectodermal dysplasia;C1970757:Tooth agenesis, selective, X-linked, 1 Pathogenic:1

May 13, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PS4_Moderate -

not provided Pathogenic:1

Sep 21, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2 T>C pathogenic variant in the EDA1 gene has been reported previously in association with X-linked hypohidrotic ectodermal dysplasia (Zhao et al., 2008), and has been observed in multiple individuals at GeneDx. The pathogenic variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1? using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. Additionally, the c.2 T>C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.74
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.33	.;.;.;.;T;.
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
PhyloP100		3.6
PROVEAN	Benign	-2.1	N;N;N;N;N;N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.98	D;D;D;B;B;B
Vest4		0.93
MutPred		1.0		Gain of glycosylation at M1 (P = 0.0043);Gain of glycosylation at M1 (P = 0.0043);Gain of glycosylation at M1 (P = 0.0043);Gain of glycosylation at M1 (P = 0.0043);Gain of glycosylation at M1 (P = 0.0043);Gain of glycosylation at M1 (P = 0.0043);
MVP		1.0
ClinPred		0.98	D
GERP RS		4.6
PromoterAI		-0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.66
gMVP		0.90
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs397516659; hg19: chrX-68836154;