18-62325363-GCGCCCGGCGGCGC-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003839.4(TNFRSF11A):c.18_30del(p.Arg7CysfsTer172) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000679 in 147,330 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000068 ( 0 hom., cov: 32)
Consequence
TNFRSF11A
NM_003839.4 frameshift
NM_003839.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.47
Genes affected
TNFRSF11A (HGNC:11908): (TNF receptor superfamily member 11a) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptors can interact with various TRAF family proteins, through which this receptor induces the activation of NF-kappa B and MAPK8/JNK. This receptor and its ligand are important regulators of the interaction between T cells and dendritic cells. This receptor is also an essential mediator for osteoclast and lymph node development. Mutations at this locus have been associated with familial expansile osteolysis, autosomal recessive osteopetrosis, and Paget disease of bone. Alternatively spliced transcript variants have been described for this locus. [provided by RefSeq, Aug 2012]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 20 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 18-62325363-GCGCCCGGCGGCGC-G is Pathogenic according to our data. Variant chr18-62325363-GCGCCCGGCGGCGC-G is described in ClinVar as [Pathogenic]. Clinvar id is 2794042.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNFRSF11A | NM_003839.4 | c.18_30del | p.Arg7CysfsTer172 | frameshift_variant | 1/10 | ENST00000586569.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNFRSF11A | ENST00000586569.3 | c.18_30del | p.Arg7CysfsTer172 | frameshift_variant | 1/10 | 1 | NM_003839.4 | P2 | |
TNFRSF11A | ENST00000269485.11 | c.18_30del | p.Arg7CysfsTer172 | frameshift_variant | 1/7 | 1 | A2 | ||
TNFRSF11A | ENST00000592013.1 | n.45_57del | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000679 AC: 1AN: 147330Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
147330
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome AF: 0.00000679 AC: 1AN: 147330Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1AN XY: 71728
GnomAD4 genome
AF:
AC:
1
AN:
147330
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
71728
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 17, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with TNFRSF11A-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg7Cysfs*172) in the TNFRSF11A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TNFRSF11A are known to be pathogenic (PMID: 10677500, 18606301, 22271396). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at