1-236409258-C-A

Position:

• chr1-236409258-C-A

Variant summary

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

The ENST00000334232.9(EDARADD):​c.104C>A​(p.Thr35Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDARADD ENST00000334232.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.61

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 18 pathogenic changes around while only 1 benign (95%) in ENST00000334232.9
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22059378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDARADD	NM_145861.4	c.104C>A	p.Thr35Asn	missense_variant	2/6	ENST00000334232.9	NP_665860.2
EDARADD	NM_080738.4	c.74C>A	p.Thr25Asn	missense_variant	2/6		NP_542776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDARADD	ENST00000334232.9	c.104C>A	p.Thr35Asn	missense_variant	2/6	1	NM_145861.4	ENSP00000335076

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

The c.104C>A (p.T35N) alteration is located in exon 2 (coding exon 2) of the EDARADD gene. This alteration results from a C to A substitution at nucleotide position 104, causing the threonine (T) at amino acid position 35 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	T;.;T;.
Eigen	Benign	-0.0070
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Uncertain	0.029	D
MutationAssessor	Uncertain	2.1	.;.;M;.
MutationTaster	Benign	0.79	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.0	.;D;N;D
REVEL	Benign	0.15
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		0.053	.;.;B;.
Vest4		0.63
MutPred		0.28		.;.;Gain of catalytic residue at T35 (P = 0.0024);.;
MVP		0.88
MPC		1.7
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.20
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-236572558;