1-236409068-TAAAAAA-TAAAAAAAAA

Variant names:

• chr1-236409068-T-TAAA
• rs772223735
• NM_145861.4:c.62-131_62-129dupAAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_145861.4(EDARADD):​c.62-131_62-129dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 333,228 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00033 (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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000426 (55/129110) while in subpopulation AFR AF = 0.00129 (45/34912). AF 95% confidence interval is 0.00099. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

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.62-131_62-129dupAAA		intron	N/A	NP_665860.2	Q8WWZ3-1
	EDARADD	NM_080738.5		c.32-131_32-129dupAAA		intron	N/A	NP_542776.1	Q8WWZ3-2
	EDARADD	NM_001422628.1		c.-5-131_-5-129dupAAA		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_62-147insAAA		intron	N/A	ENSP00000335076.4	Q8WWZ3-1
	EDARADD	ENST00000359362.6	TSL:1	c.32-148_32-147insAAA		intron	N/A	ENSP00000352320.4	Q8WWZ3-2
	EDARADD	ENST00000637660.1	TSL:5	c.-5-148_-5-147insAAA		intron	N/A	ENSP00000490347.1	A0A1B0GV26

Frequencies

GnomAD3 genomes AF: 0.000426 AC: 55 AN: 129112 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000239

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000227

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000147

Gnomad MID AF: 0.00347

Gnomad NFE AF: 0.0000497

Gnomad OTH AF: 0.000566

GnomAD4 exome AF: 0.000333 AC: 68 AN: 204118 Hom.: 0 AF XY: 0.000336 AC XY: 36 AN XY: 107170

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

African (AFR) AF: 0.00172 AC: 8 AN: 4642

American (AMR) AF: 0.000841 AC: 6 AN: 7136

Ashkenazi Jewish (ASJ) AF: 0.000169 AC: 1 AN: 5910

East Asian (EAS) AF: 0.000317 AC: 5 AN: 15772

South Asian (SAS) AF: 0.000340 AC: 4 AN: 11768

European-Finnish (FIN) AF: 0.000203 AC: 4 AN: 19692

Middle Eastern (MID) AF: 0.00115 AC: 1 AN: 866

European-Non Finnish (NFE) AF: 0.000267 AC: 34 AN: 127148

Other (OTH) AF: 0.000447 AC: 5 AN: 11184

⚠️ 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: 0.000426 AC: 55 AN: 129110 Hom.: 0 Cov.: 28 AF XY: 0.000405 AC XY: 25 AN XY: 61784

African (AFR) AF: 0.00129 AC: 45 AN: 34912

American (AMR) AF: 0.000239 AC: 3 AN: 12556

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

East Asian (EAS) AF: 0.000227 AC: 1 AN: 4398

South Asian (SAS) AF: 0.00 AC: 0 AN: 4036

European-Finnish (FIN) AF: 0.000147 AC: 1 AN: 6816

Middle Eastern (MID) AF: 0.00376 AC: 1 AN: 266

European-Non Finnish (NFE) AF: 0.0000497 AC: 3 AN: 60402

Other (OTH) AF: 0.000564 AC: 1 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

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;