rs114632254

Positions:

• chr1-236482309-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_145861.4(EDARADD):​c.308C>T​(p.Ser103Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,614,052 control chromosomes in the GnomAD database, including 704 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (48 hom., cov: 32)
  • Exomes 𝑓: 0.027 (656 hom.)
• Consequence: EDARADD NM_145861.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.62

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 -18 ACMG points.

• PM1: In a chain Ectodysplasin-A receptor-associated adapter protein (size 214) in uniprot entity EDAD_HUMAN there are 18 pathogenic changes around while only 1 benign (95%) in NM_145861.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.00474298).
• BP6: Variant 1-236482309-C-T is Benign according to our data. Variant chr1-236482309-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236482309-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0212 (3221/152182) while in subpopulation AMR AF= 0.0308 (471/15270). AF 95% confidence interval is 0.0294. There are 48 homozygotes in gnomad4. There are 1586 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 48 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDARADD	NM_145861.4	c.308C>T	p.Ser103Phe	missense_variant	6/6	ENST00000334232.9	NP_665860.2
EDARADD	NM_080738.5	c.278C>T	p.Ser93Phe	missense_variant	6/6		NP_542776.1
EDARADD	NM_001422628.1	c.242C>T	p.Ser81Phe	missense_variant	8/8		NP_001409557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDARADD	ENST00000334232.9	c.308C>T	p.Ser103Phe	missense_variant	6/6	1	NM_145861.4	ENSP00000335076.4

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3224 AN: 152064 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.00512

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0309

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0305

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0213 AC: 5347 AN: 251476 Hom.: 76 AF XY: 0.0221 AC XY: 3007 AN XY: 135912

Gnomad AFR exome AF: 0.00443

Gnomad AMR exome AF: 0.0186

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0114

Gnomad FIN exome AF: 0.0269

Gnomad NFE exome AF: 0.0301

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0272 AC: 39768 AN: 1461870 Hom.: 656 Cov.: 31 AF XY: 0.0272 AC XY: 19753 AN XY: 727238

Gnomad4 AFR exome AF: 0.00424

Gnomad4 AMR exome AF: 0.0192

Gnomad4 ASJ exome AF: 0.0124

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0117

Gnomad4 FIN exome AF: 0.0277

Gnomad4 NFE exome AF: 0.0309

Gnomad4 OTH exome AF: 0.0231

GnomAD4 genome AF: 0.0212 AC: 3221 AN: 152182 Hom.: 48 Cov.: 32 AF XY: 0.0213 AC XY: 1586 AN XY: 74390

Gnomad4 AFR AF: 0.00511

Gnomad4 AMR AF: 0.0308

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.0296

Gnomad4 NFE AF: 0.0305

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0272 Hom.: 97

Bravo AF: 0.0203

TwinsUK AF: 0.0267 AC: 99

ALSPAC AF: 0.0298 AC: 115

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0274 AC: 236

ExAC AF: 0.0211 AC: 2559

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.0317

EpiControl AF: 0.0366

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2020	This variant is associated with the following publications: (PMID: 27884173, 31796081, 23991204, 21626677, 27665865, 29705498) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive;C3541517:Ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

- -

Hypohidrotic ectodermal dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 02, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T;.;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.0047	T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	2.0	.;.;M;.
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.6	.;D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.0040	.;D;D;D
Sift4G	Uncertain	0.011	.;D;D;D
Polyphen		0.92	.;.;P;.
Vest4		0.11, 0.16
MPC		1.4
ClinPred		0.030	T
GERP RS		5.2
Varity_R		0.16
gMVP		0.29

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: rs114632254; hg19: chr1-236645609;