rs2804386

Variant names:

• chrX-69757074-A-G
• rs2804386
• NM_001399.5:c.396+140370A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001399.5(EDA):​c.396+140370A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 110,879 control chromosomes in the GnomAD database, including 4,898 homozygotes. There are 9,794 hemizygotes in GnomAD. 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: 𝑓 0.31 (4898 hom., 9794 hem., cov: 23)
• Consequence: EDA NM_001399.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.250
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.396+140370A>G		intron_variant	Intron 1 of 7	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.396+140370A>G		intron_variant	Intron 1 of 7	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes AF: 0.306 AC: 33868 AN: 110826 Hom.: 4905 Cov.: 23

Gnomad AFR AF: 0.0860

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.00307

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.584

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.344

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.305 AC: 33851 AN: 110879 Hom.: 4898 Cov.: 23 AF XY: 0.296 AC XY: 9794 AN XY: 33097

African (AFR) AF: 0.0858 AC: 2633 AN: 30683

American (AMR) AF: 0.268 AC: 2789 AN: 10402

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 1257 AN: 2618

East Asian (EAS) AF: 0.00308 AC: 11 AN: 3573

South Asian (SAS) AF: 0.259 AC: 689 AN: 2658

European-Finnish (FIN) AF: 0.383 AC: 2223 AN: 5807

Middle Eastern (MID) AF: 0.563 AC: 120 AN: 213

European-Non Finnish (NFE) AF: 0.444 AC: 23409 AN: 52736

Other (OTH) AF: 0.340 AC: 513 AN: 1511

Alfa AF: 0.365 Hom.: 3044

Bravo AF: 0.289

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.3
DANN	Benign	0.79
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2804386; hg19: chrX-68976918; COSMIC: COSV65770730;