X-69616637-C-T

Variant names:

• chrX-69616637-C-T
• rs397516660
• NM_001399.5:c.329C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001399.5(EDA):​c.329C>T​(p.Ser110Leu) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.74
• 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: Uncertain_significance. The variant received 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2577213).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA	NM_001399.5	MANE Select	c.329C>T	p.Ser110Leu	missense	Exon 1 of 8	NP_001390.1
	EDA	NM_001005609.2		c.329C>T	p.Ser110Leu	missense	Exon 1 of 8	NP_001005609.1
	EDA	NM_001440761.1		c.329C>T	p.Ser110Leu	missense	Exon 1 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.329C>T	p.Ser110Leu	missense	Exon 1 of 8	ENSP00000363680.4
	EDA	ENST00000374553.6	TSL:1	c.329C>T	p.Ser110Leu	missense	Exon 1 of 8	ENSP00000363681.2
	EDA	ENST00000524573.5	TSL:1	c.329C>T	p.Ser110Leu	missense	Exon 1 of 8	ENSP00000432585.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	0.55	N
PhyloP100		2.7
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.18
MutPred		0.42		Loss of phosphorylation at S110 (P = 0.0176)
MVP		0.96
MPC		0.69
ClinPred		0.71	D
GERP RS		3.8
Varity_R		0.52
gMVP		0.65
Mutation Taster		=87/13	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs397516660; hg19: chrX-68836481;