1-236482509-CGG-TTA

Variant names:

• chr1-236482509-CGG-TTA
• NM_145861.4:c.508_510delCGGinsTTA
• EDARADD p.Arg170Leu

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2 PP3

The NM_145861.4(EDARADD):​c.508_510delCGGinsTTA​(p.Arg170Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R170Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDARADD NM_145861.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.37
• 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 2 ACMG points.

• 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 ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant, ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive, autosomal dominant hypohidrotic ectodermal dysplasia, tooth agenesis, autosomal recessive hypohidrotic ectodermal dysplasia.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.508_510delCGGinsTTA	p.Arg170Leu	missense	N/A	NP_665860.2	Q8WWZ3-1
	EDARADD	NM_080738.5		c.478_480delCGGinsTTA	p.Arg160Leu	missense	N/A	NP_542776.1	Q8WWZ3-2
	EDARADD	NM_001422628.1		c.442_444delCGGinsTTA	p.Arg148Leu	missense	N/A	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.508_510delCGGinsTTA	p.Arg170Leu	missense	N/A	ENSP00000335076.4	Q8WWZ3-1
	EDARADD	ENST00000359362.6	TSL:1	c.478_480delCGGinsTTA	p.Arg160Leu	missense	N/A	ENSP00000352320.4	Q8WWZ3-2
	EDARADD	ENST00000637660.1	TSL:5	c.442_444delCGGinsTTA	p.Arg148Leu	missense	N/A	ENSP00000490347.1	A0A1B0GV26

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-236645809;