chr2-108894476-TTAATG-T

Position:

• chr2-108894476-TTAATG-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_022336.4(EDAR):​c.*2426_*2430delCATTA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00486 in 152,614 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0048 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0069 (0 hom.)
• Consequence: EDAR NM_022336.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.285

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00485 (738/152182) while in subpopulation NFE AF= 0.00793 (539/68008). AF 95% confidence interval is 0.00737. There are 1 homozygotes in gnomad4. There are 328 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDAR	NM_022336.4	c.*2426_*2430delCATTA		3_prime_UTR_variant	12/12	ENST00000258443.7	NP_071731.1
EDAR	XM_006712204.2	c.*2426_*2430delCATTA		3_prime_UTR_variant	11/11		XP_006712267.1
RANBP2	XM_047445367.1	c.8370+121432_8370+121436delAATGT		intron_variant			XP_047301323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDAR	ENST00000258443	c.*2426_*2430delCATTA		3_prime_UTR_variant	12/12	1	NM_022336.4	ENSP00000258443.2

Frequencies

GnomAD3 genomes AF: 0.00484 AC: 736 AN: 152064 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00792

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.00694 AC: 3 AN: 432 Hom.: 0 AF XY: 0.00385 AC XY: 1 AN XY: 260

Gnomad4 FIN exome AF: 0.00704

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00485 AC: 738 AN: 152182 Hom.: 1 Cov.: 31 AF XY: 0.00441 AC XY: 328 AN XY: 74384

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00504

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00161

Gnomad4 NFE AF: 0.00793

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00421 Hom.: 0

Bravo AF: 0.00493

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic Ectodermal Dysplasia, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs555061424; hg19: chr2-109510932;