NM_001399.5:c.599C>T

Variant names:

• chrX-70027929-C-T
• rs397516669
• NM_001399.5:c.599C>T
• EDA p.Pro200Leu

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_001399.5(EDA):​c.599C>T​(p.Pro200Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000936 in 1,068,003 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P200Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.30
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 11 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
• 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.
• PP5: Variant X-70027929-C-T is Pathogenic according to our data. Variant chrX-70027929-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3255519.Status of the report is no_assertion_criteria_provided, 0 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.599C>T	p.Pro200Leu	missense	Exon 4 of 8	NP_001390.1	Q92838-1
	EDA	NM_001005609.2		c.599C>T	p.Pro200Leu	missense	Exon 4 of 8	NP_001005609.1	Q92838-3
	EDA	NM_001440761.1		c.599C>T	p.Pro200Leu	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.599C>T	p.Pro200Leu	missense	Exon 4 of 8	ENSP00000363680.4	Q92838-1
	EDA	ENST00000374553.6	TSL:1	c.599C>T	p.Pro200Leu	missense	Exon 4 of 8	ENSP00000363681.2	Q92838-3
	EDA	ENST00000524573.5	TSL:1	c.599C>T	p.Pro200Leu	missense	Exon 4 of 8	ENSP00000432585.1	Q92838-9

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.36e-7 AC: 1 AN: 1068003 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 346479

African (AFR) AF: 0.00 AC: 0 AN: 25299

American (AMR) AF: 0.00 AC: 0 AN: 30909

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18882

East Asian (EAS) AF: 0.00 AC: 0 AN: 28302

South Asian (SAS) AF: 0.00 AC: 0 AN: 50741

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38715

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4010

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 826159

Other (OTH) AF: 0.00 AC: 0 AN: 44986

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.7	L
PhyloP100		5.3
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Varity_R		0.85
gMVP		0.91
Mutation Taster		=18/82	disease causing

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: rs397516669;

hg19: chrX-69247779;