rs397516657

Variant names:

• chrX-69616472-T-A
• rs397516657
• NM_001399.5:c.164T>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_001399.5(EDA):​c.164T>A​(p.Leu55Gln) variant causes a missense 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L55V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.33
• 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 11 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-69616471-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1465794.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• PP5: Variant X-69616472-T-A is Pathogenic according to our data. Variant chrX-69616472-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 44188.Status of the report is criteria_provided_single_submitter, 1 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.164T>A	p.Leu55Gln	missense	Exon 1 of 8	NP_001390.1	Q92838-1
	EDA	NM_001005609.2		c.164T>A	p.Leu55Gln	missense	Exon 1 of 8	NP_001005609.1	Q92838-3
	EDA	NM_001440761.1		c.164T>A	p.Leu55Gln	missense	Exon 1 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.164T>A	p.Leu55Gln	missense	Exon 1 of 8	ENSP00000363680.4	Q92838-1
	EDA	ENST00000374553.6	TSL:1	c.164T>A	p.Leu55Gln	missense	Exon 1 of 8	ENSP00000363681.2	Q92838-3
	EDA	ENST00000524573.5	TSL:1	c.164T>A	p.Leu55Gln	missense	Exon 1 of 8	ENSP00000432585.1	Q92838-9

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Likely 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
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.55	N
PhyloP100		2.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.45		Loss of stability (P = 0.1173)
MVP		1.0
MPC		1.0
ClinPred		0.99	D
GERP RS		4.8
PromoterAI		0.11	Neutral
Varity_R		0.68
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs397516657; hg19: chrX-68836316;