rs3749108

Variant names:

• chr2-108910783-C-T
• rs3749108
• NM_022336.4:c.723G>A
• EDAR p.Glu241Glu

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_022336.4(EDAR):​c.723G>A​(p.Glu241Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00681 in 1,613,166 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (78 hom.)
• Consequence: EDAR NM_022336.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.341
• Publications: 4 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 2-108910783-C-T is Benign according to our data. Variant chr2-108910783-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 463881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.341 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00476 (724/152108) while in subpopulation SAS AF = 0.0225 (108/4806). AF 95% confidence interval is 0.019. There are 6 homozygotes in GnomAd4. There are 376 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD 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.723G>A	p.Glu241Glu	synonymous	Exon 8 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.723G>A	p.Glu241Glu	synonymous	Exon 8 of 12	ENSP00000258443.2	Q9UNE0-1
	EDAR	ENST00000376651.1	TSL:2	c.819G>A	p.Glu273Glu	synonymous	Exon 7 of 11	ENSP00000365839.1	Q9UNE0-2
	EDAR	ENST00000409271.5	TSL:2	c.819G>A	p.Glu273Glu	synonymous	Exon 8 of 12	ENSP00000386371.1	Q9UNE0-2

Frequencies

GnomAD3 genomes AF: 0.00476 AC: 723 AN: 151990 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0167

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00754 AC: 1894 AN: 251210 AF XY: 0.00794

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0238

Gnomad FIN exome AF: 0.000510

Gnomad NFE exome AF: 0.00525

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.00703 AC: 10268 AN: 1461058 Hom.: 78 Cov.: 34 AF XY: 0.00737 AC XY: 5356 AN XY: 726802

African (AFR) AF: 0.00105 AC: 35 AN: 33446

American (AMR) AF: 0.00476 AC: 213 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26136

East Asian (EAS) AF: 0.0321 AC: 1275 AN: 39700

South Asian (SAS) AF: 0.0193 AC: 1664 AN: 86222

European-Finnish (FIN) AF: 0.000675 AC: 36 AN: 53334

Middle Eastern (MID) AF: 0.00464 AC: 24 AN: 5168

European-Non Finnish (NFE) AF: 0.00594 AC: 6609 AN: 1112002

Other (OTH) AF: 0.00620 AC: 374 AN: 60328

GnomAD4 genome AF: 0.00476 AC: 724 AN: 152108 Hom.: 6 Cov.: 32 AF XY: 0.00506 AC XY: 376 AN XY: 74342

African (AFR) AF: 0.00108 AC: 45 AN: 41530

American (AMR) AF: 0.00465 AC: 71 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.0168 AC: 86 AN: 5130

South Asian (SAS) AF: 0.0225 AC: 108 AN: 4806

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10590

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00550 AC: 374 AN: 67978

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00502 Hom.: 3

Bravo AF: 0.00464

Asia WGS AF: 0.0250 AC: 87 AN: 3478

EpiCase AF: 0.00632

EpiControl AF: 0.00705

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive hypohidrotic ectodermal dysplasia syndrome;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant (1)
-	-	1	HAIR MORPHOLOGY 1;C3887494: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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.0
DANN	Benign	0.63
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3749108;

hg19: chr2-109527239;