rs3749099

Variant names:

• chr2-108907953-G-A
• rs3749099
• NM_022336.4:c.870C>T

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.870C>T​(p.Pro290Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0071 in 1,613,616 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0072 (82 hom.)
• Consequence: EDAR NM_022336.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.63
• 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• 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=-0.72).
• BP6: Variant 2-108907953-G-A is Benign according to our data. Variant chr2-108907953-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00573 (872/152210) while in subpopulation SAS AF = 0.0226 (109/4816). AF 95% confidence interval is 0.0192. There are 7 homozygotes in GnomAd4. There are 449 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.870C>T	p.Pro290Pro	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.870C>T	p.Pro290Pro	synonymous	Exon 10 of 12	ENSP00000258443.2	Q9UNE0-1
	EDAR	ENST00000376651.1	TSL:2	c.966C>T	p.Pro322Pro	synonymous	Exon 9 of 11	ENSP00000365839.1	Q9UNE0-2
	EDAR	ENST00000409271.5	TSL:2	c.966C>T	p.Pro322Pro	synonymous	Exon 10 of 12	ENSP00000386371.1	Q9UNE0-2

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 871 AN: 152092 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0165

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00557

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00795 AC: 1979 AN: 248816 AF XY: 0.00830

Gnomad AFR exome AF: 0.00525

Gnomad AMR exome AF: 0.00486

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0240

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00539

Gnomad OTH exome AF: 0.00785

GnomAD4 exome AF: 0.00724 AC: 10581 AN: 1461406 Hom.: 82 Cov.: 31 AF XY: 0.00758 AC XY: 5508 AN XY: 727020

African (AFR) AF: 0.00532 AC: 178 AN: 33480

American (AMR) AF: 0.00501 AC: 224 AN: 44724

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

East Asian (EAS) AF: 0.0322 AC: 1277 AN: 39698

South Asian (SAS) AF: 0.0196 AC: 1689 AN: 86252

European-Finnish (FIN) AF: 0.000680 AC: 36 AN: 52980

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5768

European-Non Finnish (NFE) AF: 0.00601 AC: 6681 AN: 1111978

Other (OTH) AF: 0.00699 AC: 422 AN: 60390

GnomAD4 genome AF: 0.00573 AC: 872 AN: 152210 Hom.: 7 Cov.: 31 AF XY: 0.00603 AC XY: 449 AN XY: 74412

African (AFR) AF: 0.00428 AC: 178 AN: 41544

American (AMR) AF: 0.00510 AC: 78 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.0165 AC: 85 AN: 5154

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4816

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00557 AC: 379 AN: 68012

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00530 Hom.: 3

Bravo AF: 0.00579

Asia WGS AF: 0.0250 AC: 88 AN: 3478

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.6
DANN	Benign	0.75
PhyloP100		-2.6
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: rs3749099; hg19: chr2-109524409; COSMIC: COSV51503030;