rs3749098

Variant names:

• chr2-108908010-A-G
• rs3749098
• NM_022336.4:c.813T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.164
• Publications: 5 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, ClinGen, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

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.813T>C	p.Asp271Asp	synonymous	Exon 10 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.813T>C	p.Asp271Asp	synonymous	Exon 10 of 12	ENSP00000258443.2	Q9UNE0-1
	EDAR	ENST00000376651.1	TSL:2	c.909T>C	p.Asp303Asp	synonymous	Exon 9 of 11	ENSP00000365839.1	Q9UNE0-2
	EDAR	ENST00000409271.5	TSL:2	c.909T>C	p.Asp303Asp	synonymous	Exon 10 of 12	ENSP00000386371.1	Q9UNE0-2

Frequencies

GnomAD3 genomes AF: 0.00480 AC: 730 AN: 152142 Hom.: 7 Cov.: 31

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

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.: 80 Cov.: 31 AF XY: 0.00744 AC XY: 5378 AN XY: 723164

African (AFR) AF: 0.00105 AC: 35 AN: 33388

American (AMR) AF: 0.00473 AC: 211 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 38 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: 36 AN: 52864

Middle Eastern (MID) AF: 0.00522 AC: 30 AN: 5752

European-Non Finnish (NFE) AF: 0.00599 AC: 6633 AN: 1107614

Other (OTH) AF: 0.00637 AC: 383 AN: 60146

GnomAD4 genome AF: 0.00480 AC: 731 AN: 152260 Hom.: 7 Cov.: 31 AF XY: 0.00512 AC XY: 381 AN XY: 74442

African (AFR) AF: 0.00111 AC: 46 AN: 41554

American (AMR) AF: 0.00464 AC: 71 AN: 15294

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

East Asian (EAS) AF: 0.0172 AC: 89 AN: 5162

South Asian (SAS) AF: 0.0228 AC: 110 AN: 4822

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00551 AC: 375 AN: 68024

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

Alfa AF: 0.00570 Hom.: 6

Bravo AF: 0.00465

Asia WGS AF: 0.0250 AC: 89 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00723

ClinVar

ClinVar submissions as Germline

Significance: 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	Hypohidrotic ectodermal dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.060
DANN	Benign	0.41
PhyloP100		-0.16
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

Other links and lift over

dbSNP: rs3749098; hg19: chr2-109524466; COSMIC: COSV51503052;