1-236395596-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000359362.6(EDARADD):c.-34C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00518 in 1,551,398 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (35 hom.)
• Consequence: EDARADD ENST00000359362.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.72

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-236395596-C-T is Benign according to our data. Variant chr1-236395596-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1223643.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00442 (672/152138) while in subpopulation SAS AF= 0.00704 (34/4830). AF 95% confidence interval is 0.00525. There are 3 homozygotes in gnomad4. There are 340 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDARADD	NM_145861.4	c.61+1091C>T		intron_variant		ENST00000334232.9
EDARADD	NM_080738.4	c.-34C>T		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDARADD	ENST00000334232.9	c.61+1091C>T		intron_variant		1	NM_145861.4

Frequencies

GnomAD3 genomes AF: 0.00442 AC: 672 AN: 152022 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00881

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00572

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00438 AC: 668 AN: 152546 Hom.: 4 AF XY: 0.00482 AC XY: 398 AN XY: 82598

Gnomad AFR exome AF: 0.000631

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.00426

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00453

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.00576

Gnomad OTH exome AF: 0.00411

GnomAD4 exome AF: 0.00526 AC: 7367 AN: 1399260 Hom.: 35 Cov.: 31 AF XY: 0.00532 AC XY: 3678 AN XY: 691220

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.00187

Gnomad4 ASJ exome AF: 0.00326

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00573

Gnomad4 FIN exome AF: 0.00921

Gnomad4 NFE exome AF: 0.00550

Gnomad4 OTH exome AF: 0.00580

GnomAD4 genome AF: 0.00442 AC: 672 AN: 152138 Hom.: 3 Cov.: 32 AF XY: 0.00457 AC XY: 340 AN XY: 74402

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.00572

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00427 Hom.: 0

Bravo AF: 0.00373

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.36
Dann	Benign	0.93

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: rs142921113; hg19: chr1-236558896;