X-70029527-C-T

Variant names:

• chrX-70029527-C-T
• rs397516672
• NM_001399.5:c.730C>T

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.730C>T​(p.Arg244*) variant causes a stop gained 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R244R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: EDA NM_001399.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.62
• Publications: 2 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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-70029527-C-T is Pathogenic according to our data. Variant chrX-70029527-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 44205.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.730C>T	p.Arg244*	stop_gained	Exon 5 of 8	NP_001390.1
	EDA	NM_001005609.2		c.730C>T	p.Arg244*	stop_gained	Exon 5 of 8	NP_001005609.1
	EDA	NM_001440761.1		c.730C>T	p.Arg244*	stop_gained	Exon 5 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.730C>T	p.Arg244*	stop_gained	Exon 5 of 8	ENSP00000363680.4
	EDA	ENST00000374553.6	TSL:1	c.730C>T	p.Arg244*	stop_gained	Exon 5 of 8	ENSP00000363681.2
	EDA	ENST00000524573.5	TSL:1	c.730C>T	p.Arg244*	stop_gained	Exon 5 of 8	ENSP00000432585.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hypohidrotic X-linked ectodermal dysplasia (2)
1	-	-	EDA-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		1.6
Vest4		0.98
GERP RS		1.6
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs397516672; hg19: chrX-69249377;