X-69616309-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_001399.5(EDA):c.1A>G(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, single submitter P:1
• Conservation: PhyloP100: 2.45

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001399.5 (EDA) was described as [Pathogenic] in ClinVar as 44190
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-69616309-A-G is Pathogenic according to our data. Variant chrX-69616309-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1070893.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.1A>G	p.Met1?	start_lost	1/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.1A>G	p.Met1?	start_lost	1/8	1	NM_001399.5	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 14, 2020

For these reasons, this variant has been classified as Pathogenic. Disruption of the initiator codon has been observed in individual(s) with ectodermal dysplasia (PMID: 24330993, 18076698, 20979233, 11378824). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the EDA mRNA. The next in-frame methionine is located at codon 133. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Benign	20
Dann	Uncertain	0.98
FATHMM_MKL	Uncertain	0.78	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	0.96	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Benign	-1.3	N;N;N;N;N;N
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.86	P;P;P;B;B;B
Vest4		0.84
MutPred		0.99		Loss of solvent accessibility (P = 0.3103);Loss of solvent accessibility (P = 0.3103);Loss of solvent accessibility (P = 0.3103);Loss of solvent accessibility (P = 0.3103);Loss of solvent accessibility (P = 0.3103);Loss of solvent accessibility (P = 0.3103);
MVP		1.0
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.61
gMVP		0.88

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-68836153;