rs727505160

Positions:

• chrX-69616509-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001399.5(EDA):​c.201G>T​(p.Glu67Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,910 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.69

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 2 uncertain in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.201G>T	p.Glu67Asp	missense_variant	1/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.201G>T	p.Glu67Asp	missense_variant	1/8	1	NM_001399.5	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097910 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363380

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 21, 2014

The Glu67Asp variant in EDA has not been previously reported in individuals with X-linked hypohidrotic ectodermal dysplasia (XLHED) and was absent from large po pulation studiesComputational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Glu67Asp variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 11, 2020

Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; A different missense change at this residue (p.E67D) has been reported in an individual with hypodontia in the published literature (Fan et al., 2008) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;.;.;.;T;.
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	0.97	L;L;L;L;L;L
MutationTaster	Benign	0.84	N;N;N;N;N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.0	D;D;D;N;N;N
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D;D;D;.;.
Sift4G	Uncertain	0.047	D;T;T;T;T;T
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.30
MutPred		0.39		Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP		0.99
MPC		0.71
ClinPred		0.98	D
GERP RS		2.8
Varity_R		0.32
gMVP		0.81

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727505160; hg19: chrX-68836353;