rs797044436
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The ENST00000258443.7(EDAR):βc.719_722delβ(p.Lys240ArgfsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000496 in 1,613,174 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000020 ( 0 hom., cov: 31)
Exomes π: 0.0000034 ( 0 hom. )
Consequence
EDAR
ENST00000258443.7 frameshift
ENST00000258443.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.29
Genes affected
EDAR (HGNC:2895): (ectodysplasin A receptor) This gene encodes a member of the tumor necrosis factor receptor family. The encoded transmembrane protein is a receptor for the soluble ligand ectodysplasin A, and can activate the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways. It is required for the development of hair, teeth, and other ectodermal derivatives. Mutations in this gene result in autosomal dominant and recessive forms of hypohidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 2-108910783-CTCTT-C is Pathogenic according to our data. Variant chr2-108910783-CTCTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EDAR | NM_022336.4 | c.719_722del | p.Lys240ArgfsTer7 | frameshift_variant | 8/12 | ENST00000258443.7 | NP_071731.1 | |
EDAR | XM_006712204.2 | c.815_818del | p.Lys272ArgfsTer7 | frameshift_variant | 7/11 | XP_006712267.1 | ||
RANBP2 | XM_047445367.1 | c.8370+137742_8370+137745del | intron_variant | XP_047301323.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EDAR | ENST00000258443.7 | c.719_722del | p.Lys240ArgfsTer7 | frameshift_variant | 8/12 | 1 | NM_022336.4 | ENSP00000258443 | P1 | |
EDAR | ENST00000376651.1 | c.815_818del | p.Lys272ArgfsTer7 | frameshift_variant | 7/11 | 2 | ENSP00000365839 | |||
EDAR | ENST00000409271.5 | c.815_818del | p.Lys272ArgfsTer7 | frameshift_variant | 8/12 | 2 | ENSP00000386371 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151992Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251210Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135778
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461064Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 726806
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152110Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74342
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2005 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The EDAR c.719_722delAAGA (p.Lys240ArgfsTer7) variant has been reported in two studies and is found in a homozygous state in four patients from two consanguineous families with hypohidrotic ectodermal dysplasia (Naeem et al. 2005; Bashyam et al. 2012). Three of these patients were from the same family (Naeem et al. 2005). The p.Lys240ArgfsTer7 variant was also present in five unaffected heterozygous carriers, two from one family and three from the other including both parents and one sister. Control data are unavailable for this variant and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. The p.Lys240ArgfsTer7 variant has not been reported in association with autosomal dominant HED. Based on the evidence and due to the potential impact of frameshift variants, the p.Lys240ArgfsTer7 variant is classified as likely pathogenic for autosomal recessive hypohidrotic ectodermal dysplasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000005859, PMID:16029325).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at