rs3749098

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_022336.4(EDAR):c.813T>C(p.Asp271Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00687 in 1,608,416 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 7 hom., cov: 31)

Exomes 𝑓: 0.0071 ( 80 hom. )

Consequence

EDAR
NM_022336.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.164

Publications

5 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, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 2-108908010-A-G is Benign according to our data. Variant chr2-108908010-A-G is described in ClinVar as Benign. ClinVar VariationId is 463882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.164 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0048 (731/152260) while in subpopulation SAS AF = 0.0228 (110/4822). AF 95% confidence interval is 0.0194. There are 7 homozygotes in GnomAd4. There are 381 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDAR	NM_022336.4 link	c.813T>C	p.Asp271Asp	synonymous_variant	Exon 10 of 12	ENST00000258443.7	NP_071731.1	Q9UNE0-1
EDAR	XM_006712204.2 link	c.909T>C	p.Asp303Asp	synonymous_variant	Exon 9 of 11		XP_006712267.1	Q9UNE0-2
RANBP2	XM_047445367.1 link	c.8370+134964A>G		intron_variant	Intron 24 of 24		XP_047301323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EDAR	ENST00000258443.7 link	c.813T>C	p.Asp271Asp	synonymous_variant	Exon 10 of 12	1	NM_022336.4	ENSP00000258443.2	Q9UNE0-1
EDAR	ENST00000376651.1 link	c.909T>C	p.Asp303Asp	synonymous_variant	Exon 9 of 11	2		ENSP00000365839.1	Q9UNE0-2
EDAR	ENST00000409271.5 link	c.909T>C	p.Asp303Asp	synonymous_variant	Exon 10 of 12	2		ENSP00000386371.1	Q9UNE0-2

Frequencies

GnomAD3 genomes

AF:

0.00480

AC:

730

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0172

Gnomad SAS

AF:

0.0226

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00551

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00762

AC:

1890

AN:

247870

AF XY:

0.00805

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.00447

Gnomad ASJ exome

AF:

0.00180

Gnomad EAS exome

AF:

0.0240

Gnomad FIN exome

AF:

0.000510

Gnomad NFE exome

AF:

0.00534

Gnomad OTH exome

AF:

0.00771

GnomAD4 exome

AF:

0.00709

AC:

10318

AN:

1456156

Hom.:

Cov.:

AF XY:

0.00744

AC XY:

5378

AN XY:

723164

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33388

American (AMR)

AF:

0.00473

AC:

211

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.00146

AC:

AN:

26088

East Asian (EAS)

AF:

0.0321

AC:

1268

AN:

39542

South Asian (SAS)

AF:

0.0195

AC:

1684

AN:

86146

European-Finnish (FIN)

AF:

0.000681

AC:

AN:

52864

Middle Eastern (MID)

AF:

0.00522

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00599

AC:

6633

AN:

1107614

Other (OTH)

AF:

0.00637

AC:

383

AN:

60146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

525

1050

1574

2099

2624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

296

592

888

1184

1480

<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:

0.00480

AC:

731

AN:

152260

Hom.:

Cov.:

AF XY:

0.00512

AC XY:

381

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41554

American (AMR)

AF:

0.00464

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.0172

AC:

AN:

5162

South Asian (SAS)

AF:

0.0228

AC:

110

AN:

4822

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00551

AC:

375

AN:

68024

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00570

Hom.:

Bravo

AF:

0.00465

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00723

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hypohidrotic ectodermal dysplasia

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.060

(source)

DANN

Benign

0.41

PhyloP100

-0.16

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over