1-236395749-G-A

Variant names:

• chr1-236395749-G-A
• rs115678841
• NM_145861.4:c.61+1244G>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.61+1244G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,484,624 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (90 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (84 hom.)
• Consequence: EDARADD NM_145861.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.710
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-236395749-G-A is Benign according to our data. Variant chr1-236395749-G-A is described in ClinVar as [Benign]. Clinvar id is 1295013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDARADD	NM_145861.4	c.61+1244G>A		intron_variant	Intron 1 of 5	ENST00000334232.9	NP_665860.2
EDARADD	NM_080738.5	c.31+89G>A		intron_variant	Intron 1 of 5		NP_542776.1
EDARADD	NM_001422628.1	c.-5-13467G>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+1244G>A		intron_variant	Intron 1 of 5	1	NM_145861.4	ENSP00000335076.4

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2913 AN: 151718 Hom.: 90 Cov.: 32

Gnomad AFR AF: 0.0677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00505

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.00191 AC: 2545 AN: 1332792 Hom.: 84 AF XY: 0.00165 AC XY: 1088 AN XY: 657534

African (AFR) AF: 0.0744 AC: 2017 AN: 27098

American (AMR) AF: 0.00349 AC: 106 AN: 30388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23322

East Asian (EAS) AF: 0.00 AC: 0 AN: 31126

South Asian (SAS) AF: 0.000201 AC: 15 AN: 74490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33950

Middle Eastern (MID) AF: 0.00308 AC: 12 AN: 3902

European-Non Finnish (NFE) AF: 0.000120 AC: 126 AN: 1053058

Other (OTH) AF: 0.00485 AC: 269 AN: 55458

GnomAD4 genome AF: 0.0193 AC: 2927 AN: 151832 Hom.: 90 Cov.: 32 AF XY: 0.0194 AC XY: 1441 AN XY: 74206

African (AFR) AF: 0.0679 AC: 2812 AN: 41430

American (AMR) AF: 0.00504 AC: 77 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67856

Other (OTH) AF: 0.0119 AC: 25 AN: 2108

Alfa AF: 0.00382 Hom.: 0

Bravo AF: 0.0215

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 25, 2021

GeneDx

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	-0.76
CADD	Benign	10
DANN	Benign	0.91
PhyloP100		0.71
PromoterAI		0.016	Neutral
Mutation Taster		=100/0	polymorphism

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: rs115678841; hg19: chr1-236559049;