rs397516670

Variant names:

• chrX-70027984-TCCTCCAGGTCCTCCTGGTCCTCAAGGACCCCCTGG-T
• rs397516670
• NM_001399.5:c.663_697delTCCTCCTGGTCCTCAAGGACCCCCTGGCCTCCAGG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001399.5(EDA):​c.663_697delTCCTCCTGGTCCTCAAGGACCCCCTGGCCTCCAGG​(p.Pro222ThrfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA NM_001399.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32
• Publications: 3 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-70027984-TCCTCCAGGTCCTCCTGGTCCTCAAGGACCCCCTGG-T is Pathogenic according to our data. Variant chrX-70027984-TCCTCCAGGTCCTCCTGGTCCTCAAGGACCCCCTGG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 44202.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.663_697delTCCTCCTGGTCCTCAAGGACCCCCTGGCCTCCAGG	p.Pro222ThrfsTer6	frameshift	Exon 4 of 8	NP_001390.1	Q92838-1
	EDA	NM_001005609.2		c.663_697delTCCTCCTGGTCCTCAAGGACCCCCTGGCCTCCAGG	p.Pro222ThrfsTer6	frameshift	Exon 4 of 8	NP_001005609.1	Q92838-3
	EDA	NM_001440761.1		c.663_697delTCCTCCTGGTCCTCAAGGACCCCCTGGCCTCCAGG	p.Pro222ThrfsTer6	frameshift	Exon 4 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.663_697delTCCTCCTGGTCCTCAAGGACCCCCTGGCCTCCAGG	p.Pro222ThrfsTer6	frameshift	Exon 4 of 8	ENSP00000363680.4	Q92838-1
	EDA	ENST00000374553.6	TSL:1	c.663_697delTCCTCCTGGTCCTCAAGGACCCCCTGGCCTCCAGG	p.Pro222ThrfsTer6	frameshift	Exon 4 of 8	ENSP00000363681.2	Q92838-3
	EDA	ENST00000524573.5	TSL:1	c.663_697delTCCTCCTGGTCCTCAAGGACCCCCTGGCCTCCAGG	p.Pro222ThrfsTer6	frameshift	Exon 4 of 8	ENSP00000432585.1	Q92838-9

Frequencies

GnomAD3 genomes Cov.: 21

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
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: rs397516670; hg19: chrX-69247834;