rs397516665

Positions:

• chrX-70027865-GCAGGACCTCCTGGACCCAATGGCCCTCCAGGACCCC-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM4 PP5_Very_Strong

The NM_001399.5(EDA):​c.546_581del​(p.Asn185_Pro196del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000134 in 745,840 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 (★★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000013 (0 hom. 0 hem.)
• Consequence: EDA NM_001399.5 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.10

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a chain Ectodysplasin-A, secreted form (size 231) in uniprot entity EDA_HUMAN there are 151 pathogenic changes around while only 13 benign (92%) in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001399.5.
• PP5: Variant X-70027865-GCAGGACCTCCTGGACCCAATGGCCCTCCAGGACCCC-G is Pathogenic according to our data. Variant chrX-70027865-GCAGGACCTCCTGGACCCAATGGCCCTCCAGGACCCC-G is described in ClinVar as [Pathogenic]. Clinvar id is 44197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70027865-GCAGGACCTCCTGGACCCAATGGCCCTCCAGGACCCC-G is described in Lovd as [Pathogenic]. Variant chrX-70027865-GCAGGACCTCCTGGACCCAATGGCCCTCCAGGACCCC-G is described in Lovd as [Pathogenic]. Variant chrX-70027865-GCAGGACCTCCTGGACCCAATGGCCCTCCAGGACCCC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.546_581del	p.Asn185_Pro196del	inframe_deletion	4/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.546_581del	p.Asn185_Pro196del	inframe_deletion	4/8	1	NM_001399.5	P4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000134 AC: 1 AN: 745840 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 207216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 19, 2024	Criteria applied: PS2,PS4,PM4,PM2_SUP,PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 30, 2018	The p.Asn185_Pro196del (c.546_581del and c.553_588del) in-frame deletion in EDA has been identified in >10 individuals with X-linked hypohidrotic ectodermal dys plasia (de novo in at least 2 of these individuals) and segregated with disease in 1 affected relative (Bayes 1998, Monreal 1998, Schneider 2001, Lexner 2008, v an der Hout 2008, Schneider 2011, LMM data). Two different deletions (c.546_581d el and c.553_588del), which result in the same p.Asn185_Pro196del in-frame delet ion, have been reported in the individuals described above. In summary, this var iant meets criteria to be classified as pathogenic for X-linked hypohidrotic ect odermal dysplasia based upon its identification in affected individuals and de n ovo occurrences. ACMG/AMP Criteria applied: PS4; PM6_Strong; PM4; PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 27, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant does not substantially affect EDA function (PMID: 11279189). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 44197). This variant has been observed in individual(s) with ectodermal dysplasia (PMID: 9683615, 23553579, 31796081, 31924237). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.546_581del, results in the deletion of 12 amino acid(s) of the EDA protein (p.Asn185_Pro196del), but otherwise preserves the integrity of the reading frame. -

Hypohidrotic X-linked ectodermal dysplasia;C1970757:Tooth agenesis, selective, X-linked, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516665; hg19: chrX-69247715;