rs1553444917

Variant names:

• chr2-108906347-T-A
• rs1553444917
• NM_022336.4:c.985A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 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
• Publications: 0 publications found

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:9848): (RAN binding protein 2) RAN is a small GTP-binding protein of the RAS superfamily that is associated with the nuclear membrane and is thought to control a variety of cellular functions through its interactions with other proteins. This gene encodes a very large RAN-binding protein that immunolocalizes to the nuclear pore complex. The protein is a giant scaffold and mosaic cyclophilin-related nucleoporin implicated in the Ran-GTPase cycle. The encoded protein directly interacts with the E2 enzyme UBC9 and strongly enhances SUMO1 transfer from UBC9 to the SUMO1 target SP100. These findings place sumoylation at the cytoplasmic filaments of the nuclear pore complex and suggest that, for some substrates, modification and nuclear import are linked events. This gene is partially duplicated in a gene cluster that lies in a hot spot for recombination on chromosome 2q. [provided by RefSeq, Jul 2008]

RANBP2 Gene-Disease associations (from GenCC):

• familial acute necrotizing encephalopathy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain 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 VariationId is 1042627.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 34 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.72828 (below the threshold of 3.09). Trascript score misZ: 1.2871 (below the threshold of 3.09). GenCC associations: The gene is linked to ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive, ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant, autosomal dominant hypohidrotic ectodermal dysplasia, autosomal recessive hypohidrotic ectodermal dysplasia.
• 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 VariationId is 522143.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDAR	NM_022336.4	c.985A>T	p.Ile329Phe	missense_variant	Exon 11 of 12	ENST00000258443.7	NP_071731.1
EDAR	XM_006712204.2	c.1081A>T	p.Ile361Phe	missense_variant	Exon 10 of 11		XP_006712267.1
RANBP2	XM_047445367.1	c.8370+133301T>A		intron_variant	Intron 24 of 24		XP_047301323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDAR	ENST00000258443.7	c.985A>T	p.Ile329Phe	missense_variant	Exon 11 of 12	1	NM_022336.4	ENSP00000258443.2
EDAR	ENST00000376651.1	c.1081A>T	p.Ile361Phe	missense_variant	Exon 10 of 11	2		ENSP00000365839.1
EDAR	ENST00000409271.5	c.1081A>T	p.Ile361Phe	missense_variant	Exon 11 of 12	2		ENSP00000386371.1

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

Dec 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 12, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.
PhyloP100		6.8
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
Mutation Taster		=9/91	disease causing

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

Other links and lift over

dbSNP: rs1553444917; hg19: chr2-109522803;