X-70023246-G-A

Variant names:

• chrX-70023246-G-A
• rs397516664
• NM_001399.5:c.526+5G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001399.5(EDA):​c.526+5G>A variant causes a splice region, intron 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. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: EDA NM_001399.5 splice_region, intron
• Scores: Splicing: ADA: 0.9985
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.768
• Publications: 1 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-70023246-G-A is Pathogenic according to our data. Variant chrX-70023246-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 581258.Status of the report is criteria_provided_single_submitter, 1 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.526+5G>A		splice_region intron	N/A	NP_001390.1
	EDA	NM_001005609.2		c.526+5G>A		splice_region intron	N/A	NP_001005609.1
	EDA	NM_001440761.1		c.526+5G>A		splice_region intron	N/A	NP_001427690.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA	ENST00000374552.9	TSL:1 MANE Select	c.526+5G>A		splice_region intron	N/A	ENSP00000363680.4
	EDA	ENST00000374553.6	TSL:1	c.526+5G>A		splice_region intron	N/A	ENSP00000363681.2
	EDA	ENST00000524573.5	TSL:1	c.526+5G>A		splice_region intron	N/A	ENSP00000432585.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 994747 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 298385

African (AFR) AF: 0.00 AC: 0 AN: 24502

American (AMR) AF: 0.00 AC: 0 AN: 33581

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18292

East Asian (EAS) AF: 0.00 AC: 0 AN: 29356

South Asian (SAS) AF: 0.00 AC: 0 AN: 49146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39399

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3801

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 754409

Other (OTH) AF: 0.00 AC: 0 AN: 42261

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Benign	0.91
PhyloP100		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88

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

Other links and lift over

dbSNP: rs397516664; hg19: chrX-69243096;