rs74315309

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PP2PP3_StrongPP5_Moderate

The NM_145861.4(EDARADD):c.454G>A(p.Glu152Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

EDARADD
NM_145861.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 9.37

Publications

9 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: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a domain Death (size 79) in uniprot entity EDAD_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_145861.4

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 1-236482455-G-A is Pathogenic according to our data. Variant chr1-236482455-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4188.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDARADD	NM_145861.4 link	c.454G>A	p.Glu152Lys	missense_variant	Exon 6 of 6	ENST00000334232.9	NP_665860.2	Q8WWZ3-1
EDARADD	NM_080738.5 link	c.424G>A	p.Glu142Lys	missense_variant	Exon 6 of 6		NP_542776.1	Q8WWZ3-2
EDARADD	NM_001422628.1 link	c.388G>A	p.Glu130Lys	missense_variant	Exon 8 of 8		NP_001409557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDARADD	ENST00000334232.9 link	c.454G>A	p.Glu152Lys	missense_variant	Exon 6 of 6	1	NM_145861.4	ENSP00000335076.4		Q8WWZ3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251302

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111998

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000249

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive

Pathogenic:1

Jul 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PM3,PM2,PP3,PP1 -

Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

T;D;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.1

.;L;.

PhyloP100

9.4

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.4

.;D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0050

.;D;D

Sift4G

Pathogenic

0.0

.;D;D

Polyphen

1.0

.;D;.

Vest4

0.94, 0.90

MutPred

0.92

.;Gain of MoRF binding (P = 0.0141);.;

MVP

0.93

MPC

1.7

ClinPred

0.99

GERP RS

5.4

Varity_R

0.59

gMVP

0.72

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

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

Publications

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rs74315309

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over