rs966364

Variant names:

• chr1-236394628-G-A
• rs966364
• NM_145861.4:c.61+123G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-236394628-G-A
• chr1-236394628-G-C

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.61+123G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.819 in 720,314 control chromosomes in the GnomAD database, including 245,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (45731 hom., cov: 32)
  • Exomes 𝑓: 0.83 (199289 hom.)
• Consequence: EDARADD NM_145861.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.373
• Publications: 7 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 1-236394628-G-A is Benign according to our data. Variant chr1-236394628-G-A is described in ClinVar as [Benign]. Clinvar id is 439637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDARADD	NM_145861.4	c.61+123G>A		intron_variant	Intron 1 of 5	ENST00000334232.9	NP_665860.2
EDARADD	NM_001422628.1	c.-5-14588G>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.61+123G>A		intron_variant	Intron 1 of 5	1	NM_145861.4	ENSP00000335076.4
EDARADD	ENST00000637660.1	c.-5-14588G>A		intron_variant	Intron 1 of 5	5		ENSP00000490347.1
EDARADD	ENST00000439430.5	c.-5-14588G>A		intron_variant	Intron 3 of 7	3		ENSP00000405815.1

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115893 AN: 152040 Hom.: 45725 Cov.: 32

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.856

Gnomad ASJ AF: 0.847

Gnomad EAS AF: 0.919

Gnomad SAS AF: 0.917

Gnomad FIN AF: 0.814

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.841

Gnomad OTH AF: 0.776

GnomAD4 exome AF: 0.834 AC: 473767 AN: 568156 Hom.: 199289 AF XY: 0.838 AC XY: 243430 AN XY: 290574

African (AFR) AF: 0.516 AC: 7729 AN: 14974

American (AMR) AF: 0.876 AC: 13970 AN: 15944

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 11218 AN: 13294

East Asian (EAS) AF: 0.949 AC: 28848 AN: 30410

South Asian (SAS) AF: 0.903 AC: 29076 AN: 32192

European-Finnish (FIN) AF: 0.814 AC: 32537 AN: 39964

Middle Eastern (MID) AF: 0.842 AC: 2864 AN: 3402

European-Non Finnish (NFE) AF: 0.832 AC: 324119 AN: 389398

Other (OTH) AF: 0.819 AC: 23406 AN: 28578

GnomAD4 genome AF: 0.762 AC: 115935 AN: 152158 Hom.: 45731 Cov.: 32 AF XY: 0.767 AC XY: 57096 AN XY: 74394

African (AFR) AF: 0.537 AC: 22253 AN: 41460

American (AMR) AF: 0.857 AC: 13102 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.847 AC: 2938 AN: 3470

East Asian (EAS) AF: 0.919 AC: 4768 AN: 5188

South Asian (SAS) AF: 0.916 AC: 4419 AN: 4824

European-Finnish (FIN) AF: 0.814 AC: 8616 AN: 10586

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.841 AC: 57192 AN: 68020

Other (OTH) AF: 0.771 AC: 1629 AN: 2112

Alfa AF: 0.823 Hom.: 72076

Bravo AF: 0.754

Asia WGS AF: 0.860 AC: 2989 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 22, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: 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	-0.95
CADD	Benign	4.1
DANN	Benign	0.61
PhyloP100		0.37
PromoterAI		-0.0088	Neutral
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: rs966364; hg19: chr1-236557928;