Genetic Variant NM_001399.5:c.-8C>T (chrX-69616301-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001399.5(EDA):c.-8C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000935 in 1,069,252 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.4e-7 ( 0 hom. 0 hem. )

Consequence

EDA
NM_001399.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.546

Publications

1 publications found

Variant links:

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

EDA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5 link	c.-8C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	ENST00000374552.9	NP_001390.1	Q92838-1
EDA	NM_001399.5 link	c.-8C>T		5_prime_UTR_variant	Exon 1 of 8	ENST00000374552.9	NP_001390.1	Q92838-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9 link	c.-8C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	1	NM_001399.5	ENSP00000363680.4		Q92838-1
EDA	ENST00000374552.9 link	c.-8C>T		5_prime_UTR_variant	Exon 1 of 8	1	NM_001399.5	ENSP00000363680.4		Q92838-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.35e-7

AC:

AN:

1069252

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

349146

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25956

American (AMR)

AF:

0.0000308

AC:

AN:

32419

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18992

East Asian (EAS)

AF:

0.00

AC:

AN:

29173

South Asian (SAS)

AF:

0.00

AC:

AN:

52092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3375

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

832462

Other (OTH)

AF:

0.00

AC:

AN:

45175

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia

Uncertain:1

May 22, 2025

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

0.55

PromoterAI

-0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

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

Publications

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NM_001399.5:c.-8C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over