1-236409089-G-A

Variant names:

• chr1-236409089-G-A
• rs659901
• NM_145861.4:c.62-127G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145861.4(EDARADD):​c.62-127G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 437,550 control chromosomes in the GnomAD database, including 100,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (34701 hom., cov: 27)
  • Exomes 𝑓: 0.66 (65608 hom.)
• Consequence: EDARADD NM_145861.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.990
• Publications: 3 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 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 1-236409089-G-A is Benign according to our data. Variant chr1-236409089-G-A is described in ClinVar as [Benign]. Clinvar id is 1295882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDARADD	NM_145861.4	c.62-127G>A		intron_variant	Intron 1 of 5	ENST00000334232.9	NP_665860.2
EDARADD	NM_080738.5	c.32-127G>A		intron_variant	Intron 1 of 5		NP_542776.1
EDARADD	NM_001422628.1	c.-5-127G>A		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	c.62-127G>A		intron_variant	Intron 1 of 5	1	NM_145861.4	ENSP00000335076.4

Frequencies

GnomAD3 genomes AF: 0.677 AC: 101367 AN: 149752 Hom.: 34655 Cov.: 27

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.724

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.727

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.666

GnomAD4 exome AF: 0.657 AC: 188946 AN: 287718 Hom.: 65608 AF XY: 0.657 AC XY: 98907 AN XY: 150496

African (AFR) AF: 0.657 AC: 4504 AN: 6852

American (AMR) AF: 0.674 AC: 6613 AN: 9818

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 5394 AN: 8784

East Asian (EAS) AF: 0.323 AC: 7151 AN: 22138

South Asian (SAS) AF: 0.663 AC: 9816 AN: 14804

European-Finnish (FIN) AF: 0.723 AC: 22923 AN: 31698

Middle Eastern (MID) AF: 0.557 AC: 776 AN: 1392

European-Non Finnish (NFE) AF: 0.688 AC: 121189 AN: 176228

Other (OTH) AF: 0.661 AC: 10580 AN: 16004

GnomAD4 genome AF: 0.677 AC: 101463 AN: 149832 Hom.: 34701 Cov.: 27 AF XY: 0.679 AC XY: 49648 AN XY: 73164

African (AFR) AF: 0.670 AC: 27177 AN: 40544

American (AMR) AF: 0.680 AC: 10257 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2124 AN: 3456

East Asian (EAS) AF: 0.373 AC: 1898 AN: 5088

South Asian (SAS) AF: 0.675 AC: 3217 AN: 4766

European-Finnish (FIN) AF: 0.727 AC: 7239 AN: 9960

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.700 AC: 47323 AN: 67640

Other (OTH) AF: 0.668 AC: 1391 AN: 2082

Alfa AF: 0.698 Hom.: 3996

Bravo AF: 0.667

Asia WGS AF: 0.546 AC: 1832 AN: 3352

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.37
DANN	Benign	0.11
PhyloP100		-0.99
Mutation Taster		=7/93	disease causing (long InDel)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs659901; hg19: chr1-236572389; COSMIC: COSV62066165;