rs397516673

Positions:

• chrX-70029537-A-G
• chrX-70029537-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001399.5(EDA):​c.740A>G​(p.Gln247Arg) variant causes a missense, splice region change. 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. Q247H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: EDA NM_001399.5 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.38

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 Likely_pathogenic. Variant got 8 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.740A>G	p.Gln247Arg	missense_variant, splice_region_variant	5/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.740A>G	p.Gln247Arg	missense_variant, splice_region_variant	5/8	1	NM_001399.5	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 20, 2011

The Gln247Arg variant in EDA has not been reported in the literature nor previou sly identified by our laboratory. The amino acid glutamine (Gln) at position 24 7 is highly conserved across evolutionarily distant species, suggesting that a c hange to the amino acid arginine (Arg) may not be tolerated. Computational anal yses (biochemical amino acid properties, homology, PolyPhen2, SIFT, AlignGVGD) d o not provide strong support for or against pathogenicity. Without further info rmation, such as control studies, segregation data, or functional analyses, the clinical significance of this variant cannot be determined with certainty at thi s time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	.;T;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.48	T;T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.97	L;L;L;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.78	N;N;N;N;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.019	D;.;.;D;.
Sift4G	Benign	0.51	T;T;T;T;T
Polyphen		0.69	P;P;P;.;.
Vest4		0.66
MutPred		0.23		Gain of MoRF binding (P = 0.0385);Gain of MoRF binding (P = 0.0385);Gain of MoRF binding (P = 0.0385);.;.;
MVP		1.0
MPC		1.4
ClinPred		0.85	D
GERP RS		4.6
Varity_R		0.93
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516673; hg19: chrX-69249387;