rs79233817

chr1-236394442-G-Achr1-236394442-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145861.4(EDARADD):c.-3G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00841 in 1,613,906 control chromosomes in the GnomAD database, including 819 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (396 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (423 hom.)
• Consequence: EDARADD NM_145861.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.55

Genes affected

EDARADD (HGNC:14341): (EDAR associated via death domain) This gene was identified by its association with ectodermal dysplasia, a genetic disorder characterized by defective development of hair, teeth, and eccrine sweat glands. The protein encoded by this gene is a death domain-containing protein, and is found to interact with EDAR, a death domain receptor known to be required for the development of hair, teeth and other ectodermal derivatives. This protein and EDAR are coexpressed in epithelial cells during the formation of hair follicles and teeth. Through its interaction with EDAR, this protein acts as an adaptor, and links the receptor to downstream signaling pathways. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-236394442-G-A is Benign according to our data. Variant chr1-236394442-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDARADD	NM_145861.4	c.-3G>A		5_prime_UTR_variant	1/6	ENST00000334232.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDARADD	ENST00000334232.9	c.-3G>A		5_prime_UTR_variant	1/6	1	NM_145861.4
EDARADD	ENST00000439430.5	c.-5-14774G>A		intron_variant		3
EDARADD	ENST00000637660.1	c.-5-14774G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6179 AN: 152020 Hom.: 394 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0115 AC: 2883 AN: 251480 Hom.: 196 AF XY: 0.00874 AC XY: 1188 AN XY: 135908

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.00830

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.00504 AC: 7362 AN: 1461768 Hom.: 423 Cov.: 29 AF XY: 0.00448 AC XY: 3258 AN XY: 727196

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.00910

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000784

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.0408 AC: 6212 AN: 152138 Hom.: 396 Cov.: 32 AF XY: 0.0400 AC XY: 2979 AN XY: 74384

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.0153

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.00536 Hom.: 13

Bravo AF: 0.0467

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hypohidrotic Ectodermal Dysplasia, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	14
Dann	Benign	0.72

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: rs79233817; hg19: chr1-236557742;