1-236395596-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000359362.6(EDARADD):c.-34C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00518 in 1,551,398 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 35 hom. )

Consequence

EDARADD
ENST00000359362.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.72

Publications

1 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 1-236395596-C-T is Benign according to our data. Variant chr1-236395596-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1223643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00442 (672/152138) while in subpopulation SAS AF = 0.00704 (34/4830). AF 95% confidence interval is 0.00525. There are 3 homozygotes in GnomAd4. There are 340 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
EDARADD	NM_145861.4 link	c.61+1091C>T	intron_variant	Intron 1 of 5	ENST00000334232.9	NP_665860.2	Q8WWZ3-1
EDARADD	NM_080738.5 link	c.-34C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6		NP_542776.1	Q8WWZ3-2
EDARADD	NM_080738.5 link	c.-34C>T	5_prime_UTR_variant	Exon 1 of 6		NP_542776.1	Q8WWZ3-2
EDARADD	NM_001422628.1 link	c.-5-13620C>T	intron_variant	Intron 3 of 7		NP_001409557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDARADD	ENST00000334232.9 link	c.61+1091C>T		intron_variant	Intron 1 of 5	1	NM_145861.4	ENSP00000335076.4		Q8WWZ3-1

Frequencies

GnomAD3 genomes

AF:

0.00442

AC:

672

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00881

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00703

Gnomad FIN

AF:

0.0103

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.00572

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00438

AC:

668

AN:

152546

AF XY:

0.00482

show subpopulations

Gnomad AFR exome

AF:

0.000631

Gnomad AMR exome

AF:

0.00178

Gnomad ASJ exome

AF:

0.00426

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0101

Gnomad NFE exome

AF:

0.00576

Gnomad OTH exome

AF:

0.00411

GnomAD4 exome

AF:

0.00526

AC:

7367

AN:

1399260

Hom.:

Cov.:

AF XY:

0.00532

AC XY:

3678

AN XY:

691220

show subpopulations

African (AFR)

AF:

0.000598

AC:

AN:

31786

American (AMR)

AF:

0.00187

AC:

AN:

36968

Ashkenazi Jewish (ASJ)

AF:

0.00326

AC:

AN:

25186

East Asian (EAS)

AF:

0.00

AC:

AN:

36156

South Asian (SAS)

AF:

0.00573

AC:

456

AN:

79596

European-Finnish (FIN)

AF:

0.00921

AC:

401

AN:

43560

Middle Eastern (MID)

AF:

0.00895

AC:

AN:

5584

European-Non Finnish (NFE)

AF:

0.00550

AC:

5953

AN:

1082304

Other (OTH)

AF:

0.00580

AC:

337

AN:

58120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

469

938

1408

1877

2346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00442

AC:

672

AN:

152138

Hom.:

Cov.:

AF XY:

0.00457

AC XY:

340

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00130

AC:

AN:

41528

American (AMR)

AF:

0.00359

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00704

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0103

AC:

109

AN:

10598

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00572

AC:

389

AN:

67960

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

107

142

178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00427

Hom.:

Bravo

AF:

0.00373

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 05, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.36

(source)

DANN

Benign

0.93

PhyloP100

-3.7

PromoterAI

0.091

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(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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1-236395596-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over