dbSNP rs146567337: EDAR:p.Ser380Arg (chr2-108897116-T-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_022336.4(EDAR):c.1138A>C(p.Ser380Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,614,018 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00095 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00079 ( 18 hom. )

Consequence

EDAR
NM_022336.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:3

Conservation

PhyloP100: 7.67

Publications

9 publications found

Variant links:

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]

EDAR links:

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

RANBP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_022336.4

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.009544849).

BP6

Variant 2-108897116-T-G is Benign according to our data. Variant chr2-108897116-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261571.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000953 (145/152196) while in subpopulation EAS AF = 0.0244 (126/5166). AF 95% confidence interval is 0.0209. There are 3 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022336.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDAR	NM_022336.4	MANE Select	c.1138A>C	p.Ser380Arg	missense	Exon 12 of 12	NP_071731.1	Q9UNE0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDAR	ENST00000258443.7	TSL:1 MANE Select	c.1138A>C	p.Ser380Arg	missense	Exon 12 of 12	ENSP00000258443.2	Q9UNE0-1
EDAR	ENST00000376651.1	TSL:2	c.1234A>C	p.Ser412Arg	missense	Exon 11 of 11	ENSP00000365839.1	Q9UNE0-2
EDAR	ENST00000409271.5	TSL:2	c.1234A>C	p.Ser412Arg	missense	Exon 12 of 12	ENSP00000386371.1	Q9UNE0-2

Frequencies

GnomAD3 genomes

AF:

0.000934

AC:

142

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0241

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00185

AC:

464

AN:

250168

AF XY:

0.00170

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0236

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.000789

AC:

1153

AN:

1461822

Hom.:

Cov.:

AF XY:

0.000741

AC XY:

539

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0240

AC:

952

AN:

39700

South Asian (SAS)

AF:

0.000406

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000629

AC:

AN:

1112008

Other (OTH)

AF:

0.00258

AC:

156

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

158

236

315

394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000953

AC:

145

AN:

152196

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41526

American (AMR)

AF:

0.000131

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.0244

AC:

126

AN:

5166

South Asian (SAS)

AF:

0.00166

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00100

Hom.:

Bravo

AF:

0.00102

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00191

AC:

232

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant (1)

Hypohidrotic ectodermal dysplasia (1)

Non-syndromic oligodontia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.0090

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0095

MetaSVM

Uncertain

0.062

MutationAssessor

Benign

0.55

PhyloP100

7.7

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.1

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.60

MutPred

0.63

Gain of MoRF binding (P = 0.017)

MVP

0.96

MPC

1.1

ClinPred

0.046

GERP RS

5.6

Varity_R

0.54

gMVP

0.93

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over