rs3749098

chr2-108908010-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022336.4(EDAR):c.813T>C(p.Asp271=) 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:3
• Conservation: PhyloP100: -0.164

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:):

ACMG classification

Verdict is Benign. Variant got -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 id is 463882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108908010-A-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDAR	NM_022336.4	c.813T>C	p.Asp271=	synonymous_variant	10/12	ENST00000258443.7
EDAR	XM_006712204.2	c.909T>C	p.Asp303=	synonymous_variant	9/11
RANBP2	XM_047445367.1	c.8370+134964A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDAR	ENST00000258443.7	c.813T>C	p.Asp271=	synonymous_variant	10/12	1	NM_022336.4	P1
EDAR	ENST00000376651.1	c.909T>C	p.Asp303=	synonymous_variant	9/11	2
EDAR	ENST00000409271.5	c.909T>C	p.Asp303=	synonymous_variant	10/12	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

GnomAD3 exomes AF: 0.00762 AC: 1890 AN: 247870 Hom.: 21 AF XY: 0.00805 AC XY: 1081 AN XY: 134340

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 SAS exome AF: 0.0198

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

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00473

Gnomad4 ASJ exome AF: 0.00146

Gnomad4 EAS exome AF: 0.0321

Gnomad4 SAS exome AF: 0.0195

Gnomad4 FIN exome AF: 0.000681

Gnomad4 NFE exome AF: 0.00599

Gnomad4 OTH exome AF: 0.00637

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

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0172

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00551

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00590 Hom.: 5

Bravo AF: 0.00465

Asia WGS AF: 0.0250 AC: 89 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00723

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hypohidrotic ectodermal dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive hypohidrotic ectodermal dysplasia syndrome;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.060
Dann	Benign	0.41

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

Publications

LitVar

Other links and lift over

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