rs3827760

Variant names:

• chr2-108897145-A-G
• rs3827760
• NM_022336.4:c.1109T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-108897145-A-G
• chr2-108897145-A-C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_022336.4(EDAR):​c.1109T>C​(p.Val370Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 1,613,832 control chromosomes in the GnomAD database, including 23,819 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (2877 hom., cov: 32)
  • Exomes 𝑓: 0.047 (20942 hom.)
• Consequence: EDAR NM_022336.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:10 O:1
• Conservation: PhyloP100: 8.95
• Publications: 172 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, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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 autosomal recessive hypohidrotic ectodermal dysplasia, autosomal dominant hypohidrotic ectodermal dysplasia, ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant, ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive.
• BP4: Computational evidence support a benign effect (MetaRNN=9.223032E-7).
• BP6: Variant 2-108897145-A-G is Benign according to our data. Variant chr2-108897145-A-G is described in ClinVar as Benign. ClinVar VariationId is 5858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

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.1109T>C	p.Val370Ala	missense	Exon 12 of 12	NP_071731.1	Q9UNE0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDAR	ENST00000258443.7	TSL:1 MANE Select	c.1109T>C	p.Val370Ala	missense	Exon 12 of 12	ENSP00000258443.2	Q9UNE0-1
	EDAR	ENST00000376651.1	TSL:2	c.1205T>C	p.Val402Ala	missense	Exon 11 of 11	ENSP00000365839.1	Q9UNE0-2
	EDAR	ENST00000409271.5	TSL:2	c.1205T>C	p.Val402Ala	missense	Exon 12 of 12	ENSP00000386371.1	Q9UNE0-2

Frequencies

GnomAD3 genomes AF: 0.0698 AC: 10611 AN: 152038 Hom.: 2870 Cov.: 32

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.885

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0536

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00693

Gnomad OTH AF: 0.0750

GnomAD2 exomes AF: 0.152 AC: 37782 AN: 248720 AF XY: 0.127

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.511

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.919

Gnomad FIN exome AF: 0.0542

Gnomad NFE exome AF: 0.00801

Gnomad OTH exome AF: 0.0952

GnomAD4 exome AF: 0.0474 AC: 69266 AN: 1461676 Hom.: 20942 Cov.: 39 AF XY: 0.0439 AC XY: 31945 AN XY: 727124

African (AFR) AF: 0.00812 AC: 272 AN: 33480

American (AMR) AF: 0.483 AC: 21587 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 448 AN: 26136

East Asian (EAS) AF: 0.840 AC: 33343 AN: 39700

South Asian (SAS) AF: 0.00939 AC: 810 AN: 86258

European-Finnish (FIN) AF: 0.0559 AC: 2976 AN: 53210

Middle Eastern (MID) AF: 0.00867 AC: 50 AN: 5768

European-Non Finnish (NFE) AF: 0.00522 AC: 5804 AN: 1112010

Other (OTH) AF: 0.0658 AC: 3976 AN: 60392

GnomAD4 genome AF: 0.0698 AC: 10621 AN: 152156 Hom.: 2877 Cov.: 32 AF XY: 0.0779 AC XY: 5796 AN XY: 74380

African (AFR) AF: 0.0133 AC: 554 AN: 41530

American (AMR) AF: 0.273 AC: 4177 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3468

East Asian (EAS) AF: 0.885 AC: 4551 AN: 5140

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4812

European-Finnish (FIN) AF: 0.0536 AC: 568 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00693 AC: 471 AN: 67998

Other (OTH) AF: 0.0743 AC: 157 AN: 2114

Alfa AF: 0.0410 Hom.: 6605

Bravo AF: 0.0975

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.00884 AC: 76

ExAC AF: 0.129 AC: 15663

Asia WGS AF: 0.327 AC: 1136 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00522

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autosomal recessive hypohidrotic ectodermal dysplasia syndrome;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant (1)
-	-	1	Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant (1)
-	-	1	Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive (1)
-	-	1	Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant (1)
-	-	1	Hypohidrotic ectodermal dysplasia (1)
-	-	1	Hypohidrotic Ectodermal Dysplasia, Dominant (1)
1	-	-	Non-syndromic oligodontia (1)
-	-	-	Hair morphology 1, hair thickness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.031
Eigen_PC	Benign	0.089
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	9.2e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N
PhyloP100		8.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.60	N
REVEL	Uncertain	0.47
Sift	Benign	0.036	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.66	P
Vest4		0.12
MPC		0.49
ClinPred		0.044	T
GERP RS		5.6
Varity_R		0.15
gMVP		0.86
Mutation Taster		=92/8	polymorphism (auto)

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: rs3827760; hg19: chr2-109513601; COSMIC: COSV51500022;