NM_001399.5:c.11C>A

Variant names:

• chrX-69616319-C-A
• rs1396384936
• NM_001399.5:c.11C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001399.5(EDA):​c.11C>A​(p.Pro4Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000924 in 1,082,263 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.11C>A	p.Pro4Gln	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.11C>A	p.Pro4Gln	missense_variant	Exon 1 of 8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1082263 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 355225

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26249

American (AMR) AF: 0.00 AC: 0 AN: 34267

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19189

East Asian (EAS) AF: 0.00 AC: 0 AN: 29902

South Asian (SAS) AF: 0.00 AC: 0 AN: 53099

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32199

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3518

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 838249

Other (OTH) AF: 0.00 AC: 0 AN: 45591

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.39	.;.;.;.;T;.
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	0.0	N;N;N;N;N;N
PhyloP100		1.4
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.1	D;D;D;N;N;N
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.22
MutPred		0.32		Loss of catalytic residue at Y3 (P = 0.1428);Loss of catalytic residue at Y3 (P = 0.1428);Loss of catalytic residue at Y3 (P = 0.1428);Loss of catalytic residue at Y3 (P = 0.1428);Loss of catalytic residue at Y3 (P = 0.1428);Loss of catalytic residue at Y3 (P = 0.1428);
MVP		0.99
MPC		0.73
ClinPred		0.84	D
GERP RS		4.6
PromoterAI		-0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.43
gMVP		0.63
Mutation Taster		=83/17	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1396384936; hg19: chrX-68836163;