rs754851778

Variant names:

• chrX-69616336-G-A
• rs754851778
• NM_001399.5:c.28G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-69616336-G-A
• chrX-69616336-G-C
• chrX-69616336-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E10Q) has been classified as Likely benign.

• 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
• 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_benign. The variant received -3 ACMG points.

• 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.
• BS2: High AC in GnomAdExome4 at 8 XL,AD 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

African (AFR) AF: 0.00 AC: 0 AN: 26329

American (AMR) AF: 0.00 AC: 0 AN: 34916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19280

East Asian (EAS) AF: 0.00 AC: 0 AN: 30130

South Asian (SAS) AF: 0.0000933 AC: 5 AN: 53619

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34377

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3635

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 840464

Other (OTH) AF: 0.0000218 AC: 1 AN: 45806

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
PhyloP100		2.2
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
PromoterAI		0.14	Neutral
Varity_R		0.42
gMVP		0.84
Mutation Taster		=93/7	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs754851778; hg19: chrX-68836180; COSMIC: COSV58878617; COSMIC: COSV58878617;