rs121908452

Positions:

• chr2-108897182-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_022336.4(EDAR):​c.1072C>T​(p.Arg358Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,552 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EDAR NM_022336.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.47

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-108897182-G-A is Pathogenic according to our data. Variant chr2-108897182-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108897182-G-A is described in Lovd as [Pathogenic]. Variant chr2-108897182-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDAR	NM_022336.4	c.1072C>T	p.Arg358Ter	stop_gained	12/12	ENST00000258443.7
EDAR	XM_006712204.2	c.1168C>T	p.Arg390Ter	stop_gained	11/11
RANBP2	XM_047445367.1	c.8370+124136G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDAR	ENST00000258443.7	c.1072C>T	p.Arg358Ter	stop_gained	12/12	1	NM_022336.4	P1
EDAR	ENST00000376651.1	c.1168C>T	p.Arg390Ter	stop_gained	11/11	2
EDAR	ENST00000409271.5	c.1168C>T	p.Arg390Ter	stop_gained	12/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461552 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 727040

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2022	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 91 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20979233, 27305980, 21332691, 21457804, 26336973, 24884697, 24719393, 28097853, 10431241, 32906216, 18231121, 17125505) -

Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Dec 08, 2023

PS2, PS4, PM2 -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

This sequence change creates a premature translational stop signal (p.Arg358*) in the EDAR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 91 amino acid(s) of the EDAR protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypohidrotic ectodermal dysplasia (PMID: 10431241, 17125505, 24884697, 26336973, 27305980). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5852). For these reasons, this variant has been classified as Pathogenic. -

Non-syndromic oligodontia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Prosthodontics, Peking University School and Hospital of Stomatology

Apr 27, 2020

- -

Ectodermal dysplasia 10a, hypohidrotic/hair/tooth type, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.61
GERP RS		3.7

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: rs121908452; hg19: chr2-109513638; COSMIC: COSV51501770;