rs604070

Variant names:

• chr1-236482370-C-T
• rs604070
• NM_145861.4:c.369C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_145861.4(EDARADD):​c.369C>T​(p.Asp123Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,613,874 control chromosomes in the GnomAD database, including 44,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3125 hom., cov: 31)
  • Exomes 𝑓: 0.23 (41725 hom.)
• Consequence: EDARADD NM_145861.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.198
• Publications: 9 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-236482370-C-T is Benign according to our data. Variant chr1-236482370-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.198 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.247 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.369C>T	p.Asp123Asp	synonymous	Exon 6 of 6	NP_665860.2	Q8WWZ3-1
	EDARADD	NM_080738.5		c.339C>T	p.Asp113Asp	synonymous	Exon 6 of 6	NP_542776.1	Q8WWZ3-2
	EDARADD	NM_001422628.1		c.303C>T	p.Asp101Asp	synonymous	Exon 8 of 8	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.369C>T	p.Asp123Asp	synonymous	Exon 6 of 6	ENSP00000335076.4	Q8WWZ3-1
	EDARADD	ENST00000359362.6	TSL:1	c.339C>T	p.Asp113Asp	synonymous	Exon 6 of 6	ENSP00000352320.4	Q8WWZ3-2
	EDARADD	ENST00000637660.1	TSL:5	c.303C>T	p.Asp101Asp	synonymous	Exon 6 of 6	ENSP00000490347.1	A0A1B0GV26

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28067 AN: 151922 Hom.: 3128 Cov.: 31

Gnomad AFR AF: 0.0756

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.0920

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.196

GnomAD2 exomes AF: 0.200 AC: 50249 AN: 251446 AF XY: 0.205

Gnomad AFR exome AF: 0.0709

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.0905

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.233 AC: 340197 AN: 1461834 Hom.: 41725 Cov.: 35 AF XY: 0.232 AC XY: 168488 AN XY: 727220

African (AFR) AF: 0.0686 AC: 2296 AN: 33480

American (AMR) AF: 0.115 AC: 5133 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 6986 AN: 26136

East Asian (EAS) AF: 0.0891 AC: 3538 AN: 39700

South Asian (SAS) AF: 0.152 AC: 13139 AN: 86258

European-Finnish (FIN) AF: 0.269 AC: 14353 AN: 53420

Middle Eastern (MID) AF: 0.197 AC: 1137 AN: 5768

European-Non Finnish (NFE) AF: 0.252 AC: 280065 AN: 1111952

Other (OTH) AF: 0.224 AC: 13550 AN: 60396

GnomAD4 genome AF: 0.185 AC: 28059 AN: 152040 Hom.: 3125 Cov.: 31 AF XY: 0.183 AC XY: 13563 AN XY: 74302

African (AFR) AF: 0.0753 AC: 3126 AN: 41516

American (AMR) AF: 0.153 AC: 2329 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 979 AN: 3472

East Asian (EAS) AF: 0.0919 AC: 474 AN: 5160

South Asian (SAS) AF: 0.141 AC: 678 AN: 4822

European-Finnish (FIN) AF: 0.260 AC: 2743 AN: 10534

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 17020 AN: 67972

Other (OTH) AF: 0.197 AC: 416 AN: 2108

Alfa AF: 0.230 Hom.: 17938

Bravo AF: 0.172

Asia WGS AF: 0.121 AC: 420 AN: 3478

EpiCase AF: 0.251

EpiControl AF: 0.253

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive;C3541517:Ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant (1)
-	-	1	Hypohidrotic ectodermal dysplasia (1)
-	-	1	Hypohidrotic Ectodermal Dysplasia, Recessive (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.0
DANN	Benign	0.77
PhyloP100		0.20
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: rs604070; hg19: chr1-236645670; COSMIC: COSV62061161; COSMIC: COSV62061161;