rs1556098680

Variant names:

• chrX-70027943-A-T
• rs1556098680
• NM_001399.5:c.613A>T
• EDA p.Ile205Phe

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001399.5(EDA):​c.613A>T​(p.Ile205Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.44
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001399.5
• 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 X-linked hypohidrotic ectodermal dysplasia, tooth agenesis, selective, X-linked, 1, tooth agenesis.

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.613A>T	p.Ile205Phe	missense	Exon 4 of 8	NP_001390.1	Q92838-1
	EDA	NM_001005609.2		c.613A>T	p.Ile205Phe	missense	Exon 4 of 8	NP_001005609.1	Q92838-3
	EDA	NM_001440761.1		c.613A>T	p.Ile205Phe	missense	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.613A>T	p.Ile205Phe	missense	Exon 4 of 8	ENSP00000363680.4	Q92838-1
	EDA	ENST00000374553.6	TSL:1	c.613A>T	p.Ile205Phe	missense	Exon 4 of 8	ENSP00000363681.2	Q92838-3
	EDA	ENST00000524573.5	TSL:1	c.613A>T	p.Ile205Phe	missense	Exon 4 of 8	ENSP00000432585.1	Q92838-9

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.42	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.3	L
PhyloP100		3.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.39
Sift	Benign	0.040	D
Sift4G	Benign	0.57	T
Varity_R		0.92
gMVP		0.90
Mutation Taster		=52/48	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1556098680;

hg19: chrX-69247793;