rs765218801

Variant names:

• chrX-69616361-G-C
• rs765218801
• NM_001399.5:c.53G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001399.5(EDA):​c.53G>C​(p.Arg18Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,092,998 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes 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: 0.0000018 (0 hom. 1 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29
• 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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34060794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.53G>C	p.Arg18Pro	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.53G>C	p.Arg18Pro	missense_variant	Exon 1 of 8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000585 AC: 1 AN: 170895 AF XY: 0.0000164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1092998 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 1 AN XY: 360494

African (AFR) AF: 0.00 AC: 0 AN: 26350

American (AMR) AF: 0.00 AC: 0 AN: 35085

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19287

East Asian (EAS) AF: 0.00 AC: 0 AN: 30161

South Asian (SAS) AF: 0.00 AC: 0 AN: 53894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3832

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841214

Other (OTH) AF: 0.00 AC: 0 AN: 45917

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Uncertain:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	18
DANN	Uncertain	0.97
DEOGEN2	Benign	0.31	.;.;.;.;T;.
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.81	T;T;T;T;T;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.34	T;T;T;T;T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	0.0	N;N;N;N;N;N
PhyloP100		1.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.6	D;D;D;N;N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0060	D;D;D;D;.;.
Sift4G	Uncertain	0.022	D;D;D;T;T;T
Polyphen		0.99	D;D;D;P;B;P
Vest4		0.40
MutPred		0.26		Gain of glycosylation at R18 (P = 0.012);Gain of glycosylation at R18 (P = 0.012);Gain of glycosylation at R18 (P = 0.012);Gain of glycosylation at R18 (P = 0.012);Gain of glycosylation at R18 (P = 0.012);Gain of glycosylation at R18 (P = 0.012);
MVP		0.96
MPC		1.1
ClinPred		0.40	T
GERP RS		3.3
PromoterAI		0.065	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.30
gMVP		0.71
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs765218801; hg19: chrX-68836205;