rs797044436

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The ENST00000258443.7(EDAR):​c.719_722del​(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: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

EDAR
ENST00000258443.7 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.29
Variant links:
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]

Genome browser will be placed here

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
EDARNM_022336.4 linkuse as main transcriptc.719_722del p.Lys240ArgfsTer7 frameshift_variant 8/12 ENST00000258443.7 NP_071731.1
EDARXM_006712204.2 linkuse as main transcriptc.815_818del p.Lys272ArgfsTer7 frameshift_variant 7/11 XP_006712267.1
RANBP2XM_047445367.1 linkuse as main transcriptc.8370+137742_8370+137745del intron_variant XP_047301323.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EDARENST00000258443.7 linkuse as main transcriptc.719_722del p.Lys240ArgfsTer7 frameshift_variant 8/121 NM_022336.4 ENSP00000258443 P1Q9UNE0-1
EDARENST00000376651.1 linkuse as main transcriptc.815_818del p.Lys272ArgfsTer7 frameshift_variant 7/112 ENSP00000365839 Q9UNE0-2
EDARENST00000409271.5 linkuse as main transcriptc.815_818del p.Lys272ArgfsTer7 frameshift_variant 8/122 ENSP00000386371 Q9UNE0-2

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151992
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000416
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251210
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135778
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461064
Hom.:
0
AF XY:
0.00000550
AC XY:
4
AN XY:
726806
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152110
Hom.:
0
Cov.:
31
AF XY:
0.0000404
AC XY:
3
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000624
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

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 providedliterature onlyOMIMJul 01, 2005- -
Likely pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017The 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 submitterclinical testing3billionJan 03, 2022Frameshift: 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs797044436; hg19: chr2-109527239; API