X-69616330-C-A

Variant names:

• chrX-69616330-C-A
• rs1931927058
• NM_001399.5:c.22C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_001399.5(EDA):​c.22C>A​(p.Arg8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000644 in 1,086,130 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000064 (0 hom. 0 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.963
• 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 -4 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3137462).
• BS2: High AC in GnomAdExome4 at 7 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.22C>A	p.Arg8Ser	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.22C>A	p.Arg8Ser	missense_variant	Exon 1 of 8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000644 AC: 7 AN: 1086130 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 357290

African (AFR) AF: 0.00 AC: 0 AN: 26291

American (AMR) AF: 0.00 AC: 0 AN: 34683

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19259

East Asian (EAS) AF: 0.0000333 AC: 1 AN: 30066

South Asian (SAS) AF: 0.00 AC: 0 AN: 53452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3565

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839709

Other (OTH) AF: 0.000131 AC: 6 AN: 45707

GnomAD4 genome Cov.: 24

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

EDA-related disorder Uncertain:1

May 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EDA c.22C>A variant is predicted to result in the amino acid substitution p.Arg8Ser. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;.;.;.;T;.
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.77	T;T;T;T;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.31	T;T;T;T;T;T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	0.0	N;N;N;N;N;N
PhyloP100		0.96
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.76	P;P;P;P;P;P
Vest4		0.20
MutPred		0.23		Gain of phosphorylation at R8 (P = 0.0115);Gain of phosphorylation at R8 (P = 0.0115);Gain of phosphorylation at R8 (P = 0.0115);Gain of phosphorylation at R8 (P = 0.0115);Gain of phosphorylation at R8 (P = 0.0115);Gain of phosphorylation at R8 (P = 0.0115);
MVP		0.97
MPC		0.88
ClinPred		0.61	D
GERP RS		4.6
PromoterAI		0.0077	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.53
gMVP		0.83
Mutation Taster		=68/32	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1931927058; hg19: chrX-68836174;