rs1556110934

Variant names:

• chrX-70035533-C-TCAAGATGG
• rs1556110934
• NM_001399.5:c.1100delCinsTCAAGATGG

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1_Strong PM2 PP2 PP5_Moderate

The ENST00000374552.9(EDA):​c.1100delCinsTCAAGATGG​(p.Ala367ValfsTer10) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A367T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 20)
• Consequence: EDA ENST00000374552.9 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.77
• Publications: 0 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: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 1.7843 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to tooth agenesis, selective, X-linked, 1, X-linked hypohidrotic ectodermal dysplasia, tooth agenesis.
• PP5: Variant X-70035533-C-TCAAGATGG is Pathogenic according to our data. Variant chrX-70035533-C-TCAAGATGG is described in ClinVar as Pathogenic. ClinVar VariationId is 458653.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000374552.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA	NM_001399.5	MANE Select	c.1100delCinsTCAAGATGG	p.Ala367ValfsTer10	frameshift missense	Exon 8 of 8	NP_001390.1
	EDA	NM_001005609.2		c.1094delCinsTCAAGATGG	p.Ala365ValfsTer10	frameshift missense	Exon 8 of 8	NP_001005609.1
	EDA	NM_001440761.1		c.1091delCinsTCAAGATGG	p.Ala364ValfsTer10	frameshift missense	Exon 8 of 8	NP_001427690.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA	ENST00000374552.9	TSL:1 MANE Select	c.1100delCinsTCAAGATGG	p.Ala367ValfsTer10	frameshift missense	Exon 8 of 8	ENSP00000363680.4
	EDA	ENST00000374553.6	TSL:1	c.1094delCinsTCAAGATGG	p.Ala365ValfsTer10	frameshift missense	Exon 8 of 8	ENSP00000363681.2
	EDA	ENST00000524573.5	TSL:1	c.1085delCinsTCAAGATGG	p.Ala362ValfsTer10	frameshift missense	Exon 8 of 8	ENSP00000432585.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 20

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hypohidrotic X-linked ectodermal dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8

Splicing

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

Other links and lift over

dbSNP: rs1556110934; hg19: chrX-69255383;