rs1553444917

Positions:

• chr2-108906347-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_022336.4(EDAR):​c.985A>T​(p.Ile329Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I329S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EDAR NM_022336.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.76

Genes affected

EDAR (HGNC:2895): (ectodysplasin A receptor) This gene encodes a member of the tumor necrosis factor receptor family. The encoded transmembrane protein is a receptor for the soluble ligand ectodysplasin A, and can activate the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways. It is required for the development of hair, teeth, and other ectodermal derivatives. Mutations in this gene result in autosomal dominant and recessive forms of hypohidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]

RANBP2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 239) in uniprot entity EDAR_HUMAN there are 43 pathogenic changes around while only 7 benign (86%) in NM_022336.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-108906346-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1042627.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 2-108906347-T-A is Pathogenic according to our data. Variant chr2-108906347-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522143.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDAR	NM_022336.4	c.985A>T	p.Ile329Phe	missense_variant	11/12	ENST00000258443.7
EDAR	XM_006712204.2	c.1081A>T	p.Ile361Phe	missense_variant	10/11
RANBP2	XM_047445367.1	c.8370+133301T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDAR	ENST00000258443.7	c.985A>T	p.Ile329Phe	missense_variant	11/12	1	NM_022336.4	P1
EDAR	ENST00000376651.1	c.1081A>T	p.Ile361Phe	missense_variant	10/11	2
EDAR	ENST00000409271.5	c.1081A>T	p.Ile361Phe	missense_variant	11/12	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive hypohidrotic ectodermal dysplasia syndrome;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 329 of the EDAR protein (p.Ile329Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant ectodermal dysplasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 522143). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EDAR protein function. This variant disrupts the p.Ile329 amino acid residue in EDAR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Uncertain	0.55	.;D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.2	.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.3	N;N;N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.73
MutPred		0.28		.;Loss of helix (P = 0.0376);.;
MVP		0.97
MPC		1.3
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.51
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553444917; hg19: chr2-109522803;