1-236394504-G-A

Variant names:

• chr1-236394504-G-A
• rs60808129
• NM_145861.4:c.60G>A

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.60G>A​(p.Glu20Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 1,612,996 control chromosomes in the GnomAD database, including 2,822 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (259 hom., cov: 33)
  • Exomes 𝑓: 0.021 (2563 hom.)
• Consequence: EDARADD NM_145861.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00004923
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.564
• Publications: 10 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=-0.88).
• BP6: Variant 1-236394504-G-A is Benign according to our data. Variant chr1-236394504-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 282055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.564 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.285 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.60G>A	p.Glu20Glu	splice_region synonymous	Exon 1 of 6	NP_665860.2	Q8WWZ3-1
	EDARADD	NM_001422628.1		c.-5-14712G>A		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.60G>A	p.Glu20Glu	splice_region synonymous	Exon 1 of 6	ENSP00000335076.4	Q8WWZ3-1
	EDARADD	ENST00000637660.1	TSL:5	c.-5-14712G>A		intron	N/A	ENSP00000490347.1	A0A1B0GV26
	EDARADD	ENST00000439430.5	TSL:3	c.-5-14712G>A		intron	N/A	ENSP00000405815.1	B1AL55

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3441 AN: 152152 Hom.: 258 Cov.: 33

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0458

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.0767

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00648

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0467 AC: 11696 AN: 250330 AF XY: 0.0447

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.0811

Gnomad ASJ exome AF: 0.00519

Gnomad EAS exome AF: 0.313

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.00611

Gnomad OTH exome AF: 0.0291

GnomAD4 exome AF: 0.0208 AC: 30339 AN: 1460726 Hom.: 2563 Cov.: 33 AF XY: 0.0216 AC XY: 15664 AN XY: 726596

African (AFR) AF: 0.00266 AC: 89 AN: 33448

American (AMR) AF: 0.0773 AC: 3435 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.00479 AC: 125 AN: 26086

East Asian (EAS) AF: 0.320 AC: 12686 AN: 39666

South Asian (SAS) AF: 0.0630 AC: 5407 AN: 85892

European-Finnish (FIN) AF: 0.0118 AC: 632 AN: 53410

Middle Eastern (MID) AF: 0.00573 AC: 33 AN: 5764

European-Non Finnish (NFE) AF: 0.00559 AC: 6209 AN: 1111640

Other (OTH) AF: 0.0285 AC: 1723 AN: 60374

GnomAD4 genome AF: 0.0226 AC: 3436 AN: 152270 Hom.: 259 Cov.: 33 AF XY: 0.0255 AC XY: 1896 AN XY: 74458

African (AFR) AF: 0.00431 AC: 179 AN: 41562

American (AMR) AF: 0.0455 AC: 696 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.298 AC: 1535 AN: 5154

South Asian (SAS) AF: 0.0763 AC: 368 AN: 4822

European-Finnish (FIN) AF: 0.0144 AC: 153 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00648 AC: 441 AN: 68036

Other (OTH) AF: 0.0237 AC: 50 AN: 2112

Alfa AF: 0.0195 Hom.: 669

Bravo AF: 0.0275

Asia WGS AF: 0.159 AC: 552 AN: 3478

EpiCase AF: 0.00627

EpiControl AF: 0.00516

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	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 provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.0
DANN	Benign	0.73
PhyloP100		-0.56
PromoterAI		0.23	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.014
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: rs60808129; hg19: chr1-236557804; COSMIC: COSV62061788; COSMIC: COSV62061788;