NM_145861.4:c.-3G>A

Variant names:

• chr1-236394442-G-A
• rs79233817
• NM_145861.4:c.-3G>A

Variant summary

Our verdict is Benign. The variant received -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:5
• Conservation: PhyloP100: 1.55
• Publications: 3 publications found

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]

EDARADD Gene-Disease associations (from GenCC):

• ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant

  Inheritance: AD, SD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant hypohidrotic ectodermal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive hypohidrotic ectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
EDARADD	NM_145861.4	c.-3G>A		5_prime_UTR_variant	Exon 1 of 6	ENST00000334232.9	NP_665860.2
EDARADD	NM_001422628.1	c.-5-14774G>A		intron_variant	Intron 3 of 7		NP_001409557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDARADD	ENST00000334232.9	c.-3G>A		5_prime_UTR_variant	Exon 1 of 6	1	NM_145861.4	ENSP00000335076.4
EDARADD	ENST00000637660.1	c.-5-14774G>A		intron_variant	Intron 1 of 5	5		ENSP00000490347.1
EDARADD	ENST00000439430.5	c.-5-14774G>A		intron_variant	Intron 3 of 7	3		ENSP00000405815.1

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

GnomAD2 exomes AF: 0.0115 AC: 2883 AN: 251480 AF XY: 0.00874

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 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

African (AFR) AF: 0.152 AC: 5074 AN: 33460

American (AMR) AF: 0.00910 AC: 407 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00124 AC: 107 AN: 86254

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53412

Middle Eastern (MID) AF: 0.0196 AC: 113 AN: 5768

European-Non Finnish (NFE) AF: 0.000784 AC: 872 AN: 1111938

Other (OTH) AF: 0.0125 AC: 754 AN: 60390

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

African (AFR) AF: 0.140 AC: 5823 AN: 41456

American (AMR) AF: 0.0153 AC: 234 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10586

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68022

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.00857 Hom.: 35

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypohidrotic Ectodermal Dysplasia, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypohidrotic ectodermal dysplasia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		1.6
PromoterAI		-0.048	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs79233817; hg19: chr1-236557742;