rs797045087

Positions:

• chr1-236482300-G-GAAC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The ENST00000334232.9(EDARADD):​c.299_300insAAC​(p.Cys100delinsTer) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDARADD ENST00000334232.9 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.836

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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDARADD	NM_145861.4	c.299_300insAAC	p.Cys100delinsTer	stop_gained	6/6	ENST00000334232.9	NP_665860.2
EDARADD	NM_080738.4	c.269_270insAAC	p.Cys90delinsTer	stop_gained	6/6		NP_542776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDARADD	ENST00000334232.9	c.299_300insAAC	p.Cys100delinsTer	stop_gained	6/6	1	NM_145861.4	ENSP00000335076

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 13, 2015

The p.Cys100X variant in EDARADD has not been previously reported in individuals with disease and data from large population studies is insufficient to assess the frequency of the variant. This variant is an insertion of 3 bases at position c.299 and is expected to impact the protein by introducing a premature termination codon at position 100. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Truncating and loss-of-function variants have not been established as a mechanism of disease in EDARADD. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Cys100X variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs797045087; hg19: chr1-236645600;