rs751704449

Positions:

• chr1-236427430-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_145861.4(EDARADD):​c.199A>T​(p.Asn67Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: EDARADD NM_145861.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.132

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Ectodysplasin-A receptor-associated adapter protein (size 214) in uniprot entity EDAD_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_145861.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14434457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDARADD	NM_145861.4	c.199A>T	p.Asn67Tyr	missense_variant	4/6	ENST00000334232.9	NP_665860.2
EDARADD	NM_080738.4	c.169A>T	p.Asn57Tyr	missense_variant	4/6		NP_542776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDARADD	ENST00000334232.9	c.199A>T	p.Asn67Tyr	missense_variant	4/6	1	NM_145861.4	ENSP00000335076

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152062 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249694 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135020

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152062 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74272

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 14, 2020

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This sequence change replaces asparagine with tyrosine at codon 67 of the EDARADD protein (p.Asn67Tyr). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and tyrosine. This variant is present in population databases (rs751704449, ExAC 0.002%). This variant has not been reported in the literature in individuals with EDARADD-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.032	T;.;T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.0	.;.;M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.9	.;D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0050	.;D;D;D
Sift4G	Uncertain	0.0090	.;D;D;D
Polyphen		0.72	.;.;P;.
Vest4		0.28, 0.28
MutPred		0.21		.;.;Gain of catalytic residue at N67 (P = 0.0082);.;
MVP		0.85
MPC		0.74
ClinPred		0.66	D
GERP RS		0.24
Varity_R		0.12
gMVP		0.23

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: rs751704449; hg19: chr1-236590730;