rs2520397

Variant names:

• chrX-69748833-G-A
• rs2520397
• NM_001399.5:c.396+132129G>A

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+132129G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 110,957 control chromosomes in the GnomAD database, including 5,027 homozygotes. There are 10,337 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 0.32 (5027 hom., 10337 hem., cov: 22)
• Consequence: EDA NM_001399.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0510
• Publications: 2 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.396+132129G>A		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+132129G>A		intron_variant	Intron 1 of 7	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes AF: 0.321 AC: 35548 AN: 110907 Hom.: 5034 Cov.: 22

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.00310

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.356

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

GnomAD4 genome AF: 0.320 AC: 35539 AN: 110957 Hom.: 5027 Cov.: 22 AF XY: 0.311 AC XY: 10337 AN XY: 33209

African (AFR) AF: 0.132 AC: 4055 AN: 30682

American (AMR) AF: 0.276 AC: 2873 AN: 10423

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1280 AN: 2635

East Asian (EAS) AF: 0.00311 AC: 11 AN: 3534

South Asian (SAS) AF: 0.261 AC: 689 AN: 2638

European-Finnish (FIN) AF: 0.384 AC: 2241 AN: 5837

Middle Eastern (MID) AF: 0.565 AC: 121 AN: 214

European-Non Finnish (NFE) AF: 0.446 AC: 23533 AN: 52818

Other (OTH) AF: 0.352 AC: 529 AN: 1504

Alfa AF: 0.374 Hom.: 2573

Bravo AF: 0.305

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.7
DANN	Benign	0.80
PhyloP100		-0.051
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: rs2520397; hg19: chrX-68968677;