rs608825

Variant names:

• chr1-236405470-C-T
• rs608825
• NM_145861.4:c.62-3746C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_145861.4(EDARADD):​c.62-3746C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 151,966 control chromosomes in the GnomAD database, including 23,022 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (23022 hom., cov: 31)
• Consequence: EDARADD NM_145861.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.64 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.62-3746C>T		intron	N/A	NP_665860.2	Q8WWZ3-1
	EDARADD	NM_080738.5		c.32-3746C>T		intron	N/A	NP_542776.1	Q8WWZ3-2
	EDARADD	NM_001422628.1		c.-5-3746C>T		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.62-3746C>T		intron	N/A	ENSP00000335076.4	Q8WWZ3-1
	EDARADD	ENST00000359362.6	TSL:1	c.32-3746C>T		intron	N/A	ENSP00000352320.4	Q8WWZ3-2
	EDARADD	ENST00000637660.1	TSL:5	c.-5-3746C>T		intron	N/A	ENSP00000490347.1	A0A1B0GV26

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81350 AN: 151848 Hom.: 23006 Cov.: 31

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.594

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.543

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.536 AC: 81400 AN: 151966 Hom.: 23022 Cov.: 31 AF XY: 0.533 AC XY: 39575 AN XY: 74272

African (AFR) AF: 0.377 AC: 15630 AN: 41442

American (AMR) AF: 0.518 AC: 7896 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.594 AC: 2064 AN: 3472

East Asian (EAS) AF: 0.234 AC: 1204 AN: 5148

South Asian (SAS) AF: 0.515 AC: 2481 AN: 4816

European-Finnish (FIN) AF: 0.613 AC: 6477 AN: 10566

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.645 AC: 43815 AN: 67946

Other (OTH) AF: 0.544 AC: 1152 AN: 2116

Alfa AF: 0.613 Hom.: 46724

Bravo AF: 0.519

Asia WGS AF: 0.400 AC: 1392 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.37
DANN	Benign	0.69
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs608825; hg19: chr1-236568770;