1-236409068-TAAAAAA-TAAAAAAAA

Variant names:

• chr1-236409068-T-TAA
• rs772223735
• NM_145861.4:c.62-130_62-129dupAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_145861.4(EDARADD):​c.62-130_62-129dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 332,542 control chromosomes in the GnomAD database, including 113 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.023 (113 hom., cov: 28)
  • Exomes 𝑓: 0.0041 (0 hom.)
• Consequence: EDARADD NM_145861.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.336
• Publications: 0 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 11B, hypohidrotic/hair/tooth type, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant

  Inheritance: SD, AD 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0745 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145861.4. 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
	EDARADD	NM_145861.4	MANE Select	c.62-130_62-129dupAA		intron	N/A	NP_665860.2	Q8WWZ3-1
	EDARADD	NM_080738.5		c.32-130_32-129dupAA		intron	N/A	NP_542776.1	Q8WWZ3-2
	EDARADD	NM_001422628.1		c.-5-130_-5-129dupAA		intron	N/A	NP_001409557.1	A0A1B0GV26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDARADD	ENST00000334232.9	TSL:1 MANE Select	c.62-148_62-147insAA		intron	N/A	ENSP00000335076.4	Q8WWZ3-1
	EDARADD	ENST00000359362.6	TSL:1	c.32-148_32-147insAA		intron	N/A	ENSP00000352320.4	Q8WWZ3-2
	EDARADD	ENST00000637660.1	TSL:5	c.-5-148_-5-147insAA		intron	N/A	ENSP00000490347.1	A0A1B0GV26

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 2904 AN: 129054 Hom.: 114 Cov.: 28

Gnomad AFR AF: 0.0769

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000739

Gnomad FIN AF: 0.000147

Gnomad MID AF: 0.0278

Gnomad NFE AF: 0.000679

Gnomad OTH AF: 0.0193

GnomAD4 exome AF: 0.00405 AC: 825 AN: 203492 Hom.: 0 AF XY: 0.00406 AC XY: 434 AN XY: 106858

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0350 AC: 161 AN: 4604

American (AMR) AF: 0.00576 AC: 41 AN: 7112

Ashkenazi Jewish (ASJ) AF: 0.00322 AC: 19 AN: 5892

East Asian (EAS) AF: 0.00376 AC: 59 AN: 15698

South Asian (SAS) AF: 0.00392 AC: 46 AN: 11726

European-Finnish (FIN) AF: 0.00254 AC: 50 AN: 19662

Middle Eastern (MID) AF: 0.00696 AC: 6 AN: 862

European-Non Finnish (NFE) AF: 0.00301 AC: 381 AN: 126786

Other (OTH) AF: 0.00556 AC: 62 AN: 11150

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0225 AC: 2907 AN: 129050 Hom.: 113 Cov.: 28 AF XY: 0.0226 AC XY: 1397 AN XY: 61754

African (AFR) AF: 0.0769 AC: 2681 AN: 34866

American (AMR) AF: 0.0111 AC: 139 AN: 12548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3144

East Asian (EAS) AF: 0.00 AC: 0 AN: 4400

South Asian (SAS) AF: 0.000743 AC: 3 AN: 4036

European-Finnish (FIN) AF: 0.000147 AC: 1 AN: 6812

Middle Eastern (MID) AF: 0.0301 AC: 8 AN: 266

European-Non Finnish (NFE) AF: 0.000679 AC: 41 AN: 60398

Other (OTH) AF: 0.0192 AC: 34 AN: 1774

Alfa AF: 0.00 Hom.: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs772223735; hg19: chr1-236572368;