chr1-236482368-G-A

Position:

• chr1-236482368-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_145861.4(EDARADD):​c.367G>A​(p.Asp123Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. D123D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDARADD NM_145861.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.48

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_145861.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-236482368-G-A is Pathogenic according to our data. Variant chr1-236482368-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 253092.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-236482368-G-A is described in Lovd as [Pathogenic]. Variant chr1-236482368-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDARADD	NM_145861.4	c.367G>A	p.Asp123Asn	missense_variant	6/6	ENST00000334232.9
EDARADD	NM_080738.4	c.337G>A	p.Asp113Asn	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDARADD	ENST00000334232.9	c.367G>A	p.Asp123Asn	missense_variant	6/6	1	NM_145861.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

ECTODERMAL DYSPLASIA 11B, HYPOHIDROTIC/HAIR/TOOTH TYPE, AUTOSOMAL DOMINANT Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 09, 2016

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 24, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects EDARADD function (PMID: 26440664, 34219261). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 253092). This missense change has been observed in individuals with clinical features of autosomal dominant hypohidrotic ectodermal dysplasia (PMID: 26440664; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 123 of the EDARADD protein (p.Asp123Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	-0.018	T
MutationAssessor	Benign	0.81	.;L;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.9	.;D;D
REVEL	Uncertain	0.37
Sift	Benign	0.41	.;T;T
Sift4G	Benign	0.79	.;T;T
Polyphen		1.0	.;D;.
Vest4		0.74, 0.40
MutPred		0.56		.;Loss of loop (P = 0.0804);.;
MVP		0.93
MPC		1.6
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.14
gMVP		0.68

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: rs879255629; hg19: chr1-236645668;