chr1-236409068-TAAAAAA-T

Variant names:

• chr1-236409068-TAAAAAA-T
• rs772223735
• NM_145861.4:c.62-134_62-129delAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_145861.4(EDARADD):​c.62-134_62-129delAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 333,306 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 0.0000077 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000020 (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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.62-134_62-129delAAAAAA		intron	N/A	NP_665860.2	Q8WWZ3-1
	EDARADD	NM_080738.5		c.32-134_32-129delAAAAAA		intron	N/A	NP_542776.1	Q8WWZ3-2
	EDARADD	NM_001422628.1		c.-5-134_-5-129delAAAAAA		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.62-147_62-142delAAAAAA		intron	N/A	ENSP00000335076.4	Q8WWZ3-1
	EDARADD	ENST00000359362.6	TSL:1	c.32-147_32-142delAAAAAA		intron	N/A	ENSP00000352320.4	Q8WWZ3-2
	EDARADD	ENST00000637660.1	TSL:5	c.-5-147_-5-142delAAAAAA		intron	N/A	ENSP00000490347.1	A0A1B0GV26

Frequencies

GnomAD3 genomes AF: 0.00000774 AC: 1 AN: 129118 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000196 AC: 4 AN: 204188 Hom.: 0 AF XY: 0.0000187 AC XY: 2 AN XY: 107214

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

African (AFR) AF: 0.000430 AC: 2 AN: 4646

American (AMR) AF: 0.00 AC: 0 AN: 7138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5914

East Asian (EAS) AF: 0.00 AC: 0 AN: 15776

South Asian (SAS) AF: 0.00 AC: 0 AN: 11780

European-Finnish (FIN) AF: 0.0000508 AC: 1 AN: 19700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 866

European-Non Finnish (NFE) AF: 0.00000786 AC: 1 AN: 127184

Other (OTH) AF: 0.00 AC: 0 AN: 11184

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0259881), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000774 AC: 1 AN: 129118 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 61776

African (AFR) AF: 0.0000287 AC: 1 AN: 34868

American (AMR) AF: 0.00 AC: 0 AN: 12546

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4412

South Asian (SAS) AF: 0.00 AC: 0 AN: 4058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60414

Other (OTH) AF: 0.00 AC: 0 AN: 1766

Alfa AF: 0.00 Hom.: 7

Bravo AF: 0.00000378

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;