1-236409089-G-A

Position:

• chr1-236409089-G-A

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.62-127G>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

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=-0.95).
• 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/exons	MANE	Protein	UniProt
EDARADD	NM_145861.4	c.62-127G>A		intron_variant		ENST00000334232.9	NP_665860.2
EDARADD	NM_080738.4	c.32-127G>A		intron_variant			NP_542776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDARADD	ENST00000334232.9	c.62-127G>A		intron_variant		1	NM_145861.4	ENSP00000335076

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

Gnomad4 AFR exome AF: 0.657

Gnomad4 AMR exome AF: 0.674

Gnomad4 ASJ exome AF: 0.614

Gnomad4 EAS exome AF: 0.323

Gnomad4 SAS exome AF: 0.663

Gnomad4 FIN exome AF: 0.723

Gnomad4 NFE exome AF: 0.688

Gnomad4 OTH exome AF: 0.661

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

Gnomad4 AFR AF: 0.670

Gnomad4 AMR AF: 0.680

Gnomad4 ASJ AF: 0.615

Gnomad4 EAS AF: 0.373

Gnomad4 SAS AF: 0.675

Gnomad4 FIN AF: 0.727

Gnomad4 NFE AF: 0.700

Gnomad4 OTH AF: 0.668

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.37
DANN	Benign	0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs659901; hg19: chr1-236572389; COSMIC: COSV62066165;