1-236394504-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1PM2PP2BP4_Strong

The NM_145861.4(EDARADD):c.60G>C(p.Glu20Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E20E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

EDARADD
NM_145861.4 missense, splice_region

Scores

Splicing: ADA: 0.00006370

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.564

Publications

10 publications found

Variant links:

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 11A, hypohidrotic/hair/tooth type, autosomal dominant
Inheritance: AD, SD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive
Inheritance: AR 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

EDARADD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a chain Ectodysplasin-A receptor-associated adapter protein (size 214) in uniprot entity EDAD_HUMAN there are 11 pathogenic changes around while only 3 benign (79%) in NM_145861.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 9 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.1424 (below the threshold of 3.09). Trascript score misZ: 1.2505 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive hypohidrotic ectodermal dysplasia, autosomal dominant hypohidrotic ectodermal dysplasia, tooth agenesis, ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive, ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant.

BP4

Computational evidence support a benign effect (MetaRNN=0.03867224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDARADD	NM_145861.4 link	c.60G>C	p.Glu20Asp	missense_variant, splice_region_variant	Exon 1 of 6	ENST00000334232.9	NP_665860.2	Q8WWZ3-1
EDARADD	NM_001422628.1 link	c.-5-14712G>C		intron_variant	Intron 3 of 7		NP_001409557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EDARADD	ENST00000334232.9 link	c.60G>C	p.Glu20Asp	missense_variant, splice_region_variant	Exon 1 of 6	1	NM_145861.4	ENSP00000335076.4	Q8WWZ3-1
EDARADD	ENST00000637660.1 link	c.-5-14712G>C		intron_variant	Intron 1 of 5	5		ENSP00000490347.1	A0A1B0GV26
EDARADD	ENST00000439430.5 link	c.-5-14712G>C		intron_variant	Intron 3 of 7	3		ENSP00000405815.1	B1AL55

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

669

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.21

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.060

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.33

M_CAP

Benign

0.011

MetaRNN

Benign

0.039

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

-0.56

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.50

REVEL

Benign

0.11

Sift

Benign

0.37

Sift4G

Benign

0.27

Polyphen

0.0

Vest4

0.049

MutPred

0.083

Loss of MoRF binding (P = 0.1143);

MVP

0.47

MPC

0.54

ClinPred

0.17

GERP RS

-3.4

PromoterAI

0.15

Neutral

(source)

Varity_R

0.044

gMVP

0.042

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000064

dbscSNV1_RF

Benign

0.010

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

Publications

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1-236394504-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over