X-69616310-T-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001399.5(EDA):​c.2T>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: 3.56

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 3 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-G is Pathogenic according to our data. Variant chrX-69616310-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 2737240.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-69616310-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.2T>G	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>G	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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Aug 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 11378824, 18076698, 20979233, 24330993). This variant is not present in population databases (gnomAD 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	0.74	D
BayesDel_noAF	Pathogenic	0.75
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.31	.;.;.;.;T;.
FATHMM_MKL	Benign	0.55	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	1.0	D
PROVEAN	Benign	-2.3	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		0.99	D;D;D;P;P;P
Vest4		0.94
MutPred		0.99		Gain of methylation at M1 (P = 0.0073);Gain of methylation at M1 (P = 0.0073);Gain of methylation at M1 (P = 0.0073);Gain of methylation at M1 (P = 0.0073);Gain of methylation at M1 (P = 0.0073);Gain of methylation at M1 (P = 0.0073);
MVP		1.0
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.89
gMVP		0.96

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-68836154;