1-236409175-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145861.4(EDARADD):c.62-41A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,536,620 control chromosomes in the GnomAD database, including 252,163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (22076 hom., cov: 31)
  • Exomes 𝑓: 0.57 (230087 hom.)
• Consequence: EDARADD NM_145861.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.278

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-236409175-A-G is Benign according to our data. Variant chr1-236409175-A-G is described in ClinVar as [Benign]. Clinvar id is 1255368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDARADD	NM_145861.4	c.62-41A>G		intron_variant		ENST00000334232.9
EDARADD	NM_080738.4	c.32-41A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDARADD	ENST00000334232.9	c.62-41A>G		intron_variant		1	NM_145861.4

Frequencies

GnomAD3 genomes AF: 0.533 AC: 80908 AN: 151762 Hom.: 22044 Cov.: 31

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.590

Gnomad OTH AF: 0.538

GnomAD3 exomes AF: 0.525 AC: 127524 AN: 242702 Hom.: 34804 AF XY: 0.529 AC XY: 69358 AN XY: 131034

Gnomad AFR exome AF: 0.477

Gnomad AMR exome AF: 0.437

Gnomad ASJ exome AF: 0.525

Gnomad EAS exome AF: 0.260

Gnomad SAS exome AF: 0.491

Gnomad FIN exome AF: 0.599

Gnomad NFE exome AF: 0.594

Gnomad OTH exome AF: 0.551

GnomAD4 exome AF: 0.570 AC: 789027 AN: 1384740 Hom.: 230087 Cov.: 19 AF XY: 0.568 AC XY: 393499 AN XY: 692358

Gnomad4 AFR exome AF: 0.477

Gnomad4 AMR exome AF: 0.445

Gnomad4 ASJ exome AF: 0.528

Gnomad4 EAS exome AF: 0.205

Gnomad4 SAS exome AF: 0.493

Gnomad4 FIN exome AF: 0.596

Gnomad4 NFE exome AF: 0.599

Gnomad4 OTH exome AF: 0.552

GnomAD4 genome AF: 0.533 AC: 81006 AN: 151880 Hom.: 22076 Cov.: 31 AF XY: 0.531 AC XY: 39435 AN XY: 74252

Gnomad4 AFR AF: 0.480

Gnomad4 AMR AF: 0.489

Gnomad4 ASJ AF: 0.522

Gnomad4 EAS AF: 0.263

Gnomad4 SAS AF: 0.496

Gnomad4 FIN AF: 0.599

Gnomad4 NFE AF: 0.590

Gnomad4 OTH AF: 0.540

Alfa AF: 0.553 Hom.: 4951

Bravo AF: 0.518

Asia WGS AF: 0.420 AC: 1462 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.1
Dann	Benign	0.65

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

LitVar

Other links and lift over

dbSNP: rs669710; hg19: chr1-236572475; COSMIC: COSV62061755;