rs397516669

Variant names:

• chrX-70027929-C-A
• rs397516669
• NM_001399.5:c.599C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-70027929-C-A
• chrX-70027929-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_001399.5(EDA):​c.599C>A​(p.Pro200Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P200L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.30
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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-70027929-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3255519.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.599C>A	p.Pro200Gln	missense_variant	Exon 4 of 8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.599C>A	p.Pro200Gln	missense_variant	Exon 4 of 8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1068001 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 346477

African (AFR) AF: 0.00 AC: 0 AN: 25299

American (AMR) AF: 0.00 AC: 0 AN: 30909

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18882

East Asian (EAS) AF: 0.00 AC: 0 AN: 28302

South Asian (SAS) AF: 0.00 AC: 0 AN: 50741

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4010

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 826158

Other (OTH) AF: 0.00 AC: 0 AN: 44986

GnomAD4 genome Cov.: 21

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

The Pro200Gln variant has not been reported in the literature nor previously ide ntified in our laboratory. The amino acid proline (Pro) at position 200 is high ly conserved across evolutionarily distant species. Additionally, computational analysis (AlignGVGD and SIFT) predict that the change to a glutamine (Gln) at t his position may impact the protein. However, this information is not predictiv e enough to assume pathogenicity. In the absence of additional information, such as control studies, segregation data, and functional analysis, the clinical sig nificance of this variant cannot be determined at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	.;T;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.63	D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	0.31	N;N;N;.;.
PhyloP100		5.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.10	N;N;N;N;.
REVEL	Uncertain	0.49
Sift	Benign	0.036	D;.;.;T;.
Sift4G	Uncertain	0.056	T;D;T;T;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.47
MutPred		0.33		Loss of glycosylation at P200 (P = 0.0536);Loss of glycosylation at P200 (P = 0.0536);Loss of glycosylation at P200 (P = 0.0536);.;.;
MVP		0.95
MPC		0.73
ClinPred		0.81	D
GERP RS		4.7
Varity_R		0.76
gMVP		0.89
Mutation Taster		=9/91	disease causing

Splicing

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

Other links and lift over

dbSNP: rs397516669; hg19: chrX-69247779;