X-69616336-G-A

Variant names:

• chrX-69616336-G-A
• NM_001399.5:c.28G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001399.5(EDA):​c.28G>A​(p.Glu10Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000735 in 1,088,556 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000073 (0 hom. 2 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

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_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.28G>A	p.Glu10Lys	missense_variant	Exon 1 of 8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.28G>A	p.Glu10Lys	missense_variant	Exon 1 of 8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000735 AC: 8 AN: 1088556 Hom.: 0 Cov.: 31 AF XY: 0.00000558 AC XY: 2 AN XY: 358600

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000933

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 15, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;.;.;.;T;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.0	N;N;N;N;N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.73	N;N;N;N;N;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0050	D;D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;T;T;T
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.16
MutPred		0.21		Gain of methylation at E10 (P = 0.0071);Gain of methylation at E10 (P = 0.0071);Gain of methylation at E10 (P = 0.0071);Gain of methylation at E10 (P = 0.0071);Gain of methylation at E10 (P = 0.0071);Gain of methylation at E10 (P = 0.0071);
MVP		0.98
MPC		0.88
ClinPred		0.67	D
GERP RS		4.6
Varity_R		0.42
gMVP		0.84

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-68836180; COSMIC: COSV58878617; COSMIC: COSV58878617;