rs1553448523

Variant names:

• chr2-108930128-G-A
• rs1553448523
• NM_022336.4:c.166C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_022336.4(EDAR):​c.166C>T​(p.Pro56Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P56R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EDAR NM_022336.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.11
• 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: Uncertain_significance. The variant received 4 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 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDAR	NM_022336.4	c.166C>T	p.Pro56Ser	missense_variant	Exon 3 of 12	ENST00000258443.7	NP_071731.1
EDAR	XM_006712204.2	c.166C>T	p.Pro56Ser	missense_variant	Exon 3 of 11		XP_006712267.1
RANBP2	XM_047445367.1	c.8370+157082G>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.166C>T	p.Pro56Ser	missense_variant	Exon 3 of 12	1	NM_022336.4	ENSP00000258443.2
EDAR	ENST00000376651.1	c.166C>T	p.Pro56Ser	missense_variant	Exon 3 of 11	2		ENSP00000365839.1
EDAR	ENST00000409271.5	c.166C>T	p.Pro56Ser	missense_variant	Exon 4 of 12	2		ENSP00000386371.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461376 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726984

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111854

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Aug 03, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with serine at codon 56 of the EDAR protein (p.Pro56Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with EDAR-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	.;D;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.4	M;M;M
PhyloP100		9.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Uncertain	0.64
Sift	Benign	0.044	D;T;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.78
MutPred		0.36		Gain of phosphorylation at P56 (P = 0.0704);Gain of phosphorylation at P56 (P = 0.0704);Gain of phosphorylation at P56 (P = 0.0704);
MVP		0.98
MPC		0.94
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.15
gMVP		0.56
Mutation Taster		=32/68	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: rs1553448523; hg19: chr2-109546584;