X-70033515-A-C

Position:

• chrX-70033515-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The ENST00000374552.9(EDA):​c.911A>C​(p.Tyr304Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y304D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: EDA ENST00000374552.9 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.72

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 12 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000374552.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-70033515-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant X-70033515-A-C is Pathogenic according to our data. Variant chrX-70033515-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228258.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.911A>C	p.Tyr304Ser	missense_variant	7/8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.911A>C	p.Tyr304Ser	missense_variant	7/8	1	NM_001399.5	ENSP00000363680.4
EDA	ENST00000374553.6	c.911A>C	p.Tyr304Ser	missense_variant	7/8	1		ENSP00000363681.2
EDA	ENST00000524573.5	c.902A>C	p.Tyr301Ser	missense_variant	7/8	1		ENSP00000432585.1
EDA	ENST00000616899.1	c.515A>C	p.Tyr172Ser	missense_variant	6/7	5		ENSP00000481963.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 21, 2015

The p.Tyr304Ser variant in EDA has not been previously reported in families with clinical features of XLHED or in large population studies. However, two differe nt amino acid changes at the same position (Tyr304Cys, Tyr304Asn) have been iden tified in 3 individuals with X-linked hypohidrotic ectodermal dysplasia (RamaDev i 2008, Schneider 2011, Dietz 2013), suggesting that variants at this position a re not tolerated. Computational prediction tools and conservation analysis sugge st that the p.Tyr304Ser variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additi onal studies are required to fully establish its clinical significance, given th e presence of this variant in this individual's affected brother and the intoler ance of the p.Tyr304 residue to variation, the p.Tyr304Ser variant is likely pat hogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	.;D;.;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.3	D;D;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0060	D;.;.;.
Sift4G	Benign	0.16	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.93
MutPred		0.83		Loss of catalytic residue at I303 (P = 0.0536);Loss of catalytic residue at I303 (P = 0.0536);.;.;
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		5.5
Varity_R		1.0
gMVP		0.98

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657642; hg19: chrX-69253365;