rs397516674

Variant names:

• chrX-70030520-G-A
• rs397516674
• NM_001399.5:c.793G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_001399.5(EDA):​c.793G>A​(p.Asp265Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D265G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: EDA NM_001399.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.42
• 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-70033398-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179264.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 1.7843 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to tooth agenesis, selective, X-linked, 1, X-linked hypohidrotic ectodermal dysplasia, tooth agenesis.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.793G>A	p.Asp265Asn	missense_variant, splice_region_variant	Exon 6 of 8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.793G>A	p.Asp265Asn	missense_variant, splice_region_variant	Exon 6 of 8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 20, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Asp265Asn v ariant in EDA has not been reported in the literature nor previously identified by our laboratory. Aspartic acid (Asp) at position 265 is conserved across evol utionarily distant species, suggesting that a change to the amino acid may not b e tolerated. In addition, two computational analyses (PolyPhen2 and SIFT) sugge st that the change to asparagine (Asn) at this position may impact the protein. Furthermore, this variant is located near the conserved splice sequence and spl ice predictor programs also suggest that this variant may impact the protein spl icing. However, the accuracy of these predicative tools is unknown and therefor e, not predictive enough to assume pathogenicity. Without further information, such as control studies, functional analyses, or segregation data, the clinical significance of this variant cannot be determined at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;M;.;.
PhyloP100		8.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.10	N;N;N;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.028	D;.;D;.
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.99	D;D;.;.
Vest4		0.84
MutPred		0.46		Gain of MoRF binding (P = 0.0356);Gain of MoRF binding (P = 0.0356);.;.;
MVP		0.99
MPC		1.8
ClinPred		0.85	D
GERP RS		5.0
Varity_R		0.90
gMVP		0.91
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98

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

Other links and lift over

dbSNP: rs397516674; hg19: chrX-69250370;