NM_145861.4:c.62-129dupA

Variant names:

• chr1-236409068-T-TA
• rs772223735
• NM_145861.4:c.62-129dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_145861.4(EDARADD):​c.62-129dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0564 in 332,858 control chromosomes in the GnomAD database, including 768 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.069 (757 hom., cov: 28)
  • Exomes 𝑓: 0.048 (11 hom.)
• Consequence: EDARADD NM_145861.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.336
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 1-236409068-T-TA is Benign according to our data. Variant chr1-236409068-T-TA is described in ClinVar as [Benign]. Clinvar id is 1255321.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDARADD	NM_145861.4	c.62-129dupA		intron_variant	Intron 1 of 5	ENST00000334232.9	NP_665860.2
EDARADD	NM_080738.5	c.32-129dupA		intron_variant	Intron 1 of 5		NP_542776.1
EDARADD	NM_001422628.1	c.-5-129dupA		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.62-148_62-147insA		intron_variant	Intron 1 of 5	1	NM_145861.4	ENSP00000335076.4

Frequencies

GnomAD3 genomes AF: 0.0691 AC: 8919 AN: 129002 Hom.: 756 Cov.: 28

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.0335

Gnomad AMR AF: 0.0307

Gnomad ASJ AF: 0.0258

Gnomad EAS AF: 0.0384

Gnomad SAS AF: 0.00862

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.0208

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0585

GnomAD4 exome AF: 0.0483 AC: 9854 AN: 203858 Hom.: 11 AF XY: 0.0492 AC XY: 5265 AN XY: 107028

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.125 AC: 578 AN: 4632

American (AMR) AF: 0.0539 AC: 384 AN: 7122

Ashkenazi Jewish (ASJ) AF: 0.0462 AC: 273 AN: 5906

East Asian (EAS) AF: 0.0519 AC: 816 AN: 15734

South Asian (SAS) AF: 0.0517 AC: 608 AN: 11758

European-Finnish (FIN) AF: 0.0330 AC: 649 AN: 19692

Middle Eastern (MID) AF: 0.0404 AC: 35 AN: 866

European-Non Finnish (NFE) AF: 0.0463 AC: 5877 AN: 126976

Other (OTH) AF: 0.0567 AC: 634 AN: 11172

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0692 AC: 8930 AN: 129000 Hom.: 757 Cov.: 28 AF XY: 0.0672 AC XY: 4145 AN XY: 61722

African (AFR) AF: 0.206 AC: 7167 AN: 34840

American (AMR) AF: 0.0307 AC: 385 AN: 12550

Ashkenazi Jewish (ASJ) AF: 0.0258 AC: 81 AN: 3142

East Asian (EAS) AF: 0.0387 AC: 170 AN: 4392

South Asian (SAS) AF: 0.00892 AC: 36 AN: 4036

European-Finnish (FIN) AF: 0.0137 AC: 93 AN: 6812

Middle Eastern (MID) AF: 0.0188 AC: 5 AN: 266

European-Non Finnish (NFE) AF: 0.0143 AC: 861 AN: 60386

Other (OTH) AF: 0.0593 AC: 105 AN: 1770

Alfa AF: 0.00315 Hom.: 7

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 21, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs772223735; hg19: chr1-236572368;