rs61761321

chr2-108929235-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_022336.4(EDAR):c.319A>G(p.Met107Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,614,160 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M107I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (170 hom.)
• Consequence: EDAR NM_022336.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: 0.582

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 Benign. Variant got -18 ACMG points.

• PM1: In a disulfide_bond (size 20) in uniprot entity EDAR_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_022336.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0023139715).
• BP6: Variant 2-108929235-T-C is Benign according to our data. Variant chr2-108929235-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 261572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDAR	NM_022336.4	c.319A>G	p.Met107Val	missense_variant	4/12	ENST00000258443.7
EDAR	XM_006712204.2	c.319A>G	p.Met107Val	missense_variant	4/11
RANBP2	XM_047445367.1	c.8370+156189T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDAR	ENST00000258443.7	c.319A>G	p.Met107Val	missense_variant	4/12	1	NM_022336.4	P1
EDAR	ENST00000376651.1	c.319A>G	p.Met107Val	missense_variant	4/11	2
EDAR	ENST00000409271.5	c.319A>G	p.Met107Val	missense_variant	5/12	2

Frequencies

GnomAD3 genomes AF: 0.00395 AC: 601 AN: 152246 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00859 AC: 2159 AN: 251278 Hom.: 139 AF XY: 0.00791 AC XY: 1075 AN XY: 135868

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.114

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00251 AC: 3665 AN: 1461796 Hom.: 170 Cov.: 32 AF XY: 0.00245 AC XY: 1778 AN XY: 727196

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0817

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00522

GnomAD4 genome AF: 0.00393 AC: 599 AN: 152364 Hom.: 38 Cov.: 33 AF XY: 0.00444 AC XY: 331 AN XY: 74518

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00366 Hom.: 40

Bravo AF: 0.00469

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00764 AC: 927

Asia WGS AF: 0.0330 AC: 113 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

- -

Hypohidrotic Ectodermal Dysplasia, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypohidrotic ectodermal dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	14
Dann	Benign	0.90
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.67	D
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.57	N;N;N
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.26	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.53	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.36
MVP		0.89
MPC		0.29
ClinPred		0.0027	T
GERP RS		4.1
Varity_R		0.12
gMVP		0.30

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: rs61761321; hg19: chr2-109545691; COSMIC: COSV51504814;