chr1-236409258-C-A

Variant names:

• chr1-236409258-C-A
• NM_145861.4:c.104C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_145861.4(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 NM_145861.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.61
• Publications: 0 publications found

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]

EDARADD Gene-Disease associations (from GenCC):

• ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant hypohidrotic ectodermal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive hypohidrotic ectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 9 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.1424 (below the threshold of 3.09). Trascript score misZ: 1.2505 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive hypohidrotic ectodermal dysplasia, autosomal dominant hypohidrotic ectodermal dysplasia, tooth agenesis, ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive, ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22059378).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145861.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDARADD	NM_145861.4	MANE Select	c.104C>A	p.Thr35Asn	missense	Exon 2 of 6	NP_665860.2	Q8WWZ3-1
	EDARADD	NM_080738.5		c.74C>A	p.Thr25Asn	missense	Exon 2 of 6	NP_542776.1	Q8WWZ3-2
	EDARADD	NM_001422628.1		c.38C>A	p.Thr13Asn	missense	Exon 4 of 8	NP_001409557.1	A0A1B0GV26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDARADD	ENST00000334232.9	TSL:1 MANE Select	c.104C>A	p.Thr35Asn	missense	Exon 2 of 6	ENSP00000335076.4	Q8WWZ3-1
	EDARADD	ENST00000359362.6	TSL:1	c.74C>A	p.Thr25Asn	missense	Exon 2 of 6	ENSP00000352320.4	Q8WWZ3-2
	EDARADD	ENST00000637660.1	TSL:5	c.38C>A	p.Thr13Asn	missense	Exon 2 of 6	ENSP00000490347.1	A0A1B0GV26

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.0070
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.029	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	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
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

hg19: chr1-236572558;