chr18-62325353-A-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_003839.4(TNFRSF11A):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000196 in 1,021,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000068 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000011 ( 0 hom. )
Consequence
TNFRSF11A
NM_003839.4 start_lost
NM_003839.4 start_lost
Scores
2
3
6
Clinical Significance
Conservation
PhyloP100: 3.07
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 10 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNFRSF11A | NM_003839.4 | c.1A>G | p.Met1? | start_lost | 1/10 | ENST00000586569.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNFRSF11A | ENST00000586569.3 | c.1A>G | p.Met1? | start_lost | 1/10 | 1 | NM_003839.4 | P2 | |
TNFRSF11A | ENST00000269485.11 | c.1A>G | p.Met1? | start_lost | 1/7 | 1 | A2 | ||
TNFRSF11A | ENST00000592013.1 | n.28A>G | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000681 AC: 1AN: 146818Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
1
AN:
146818
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:
GnomAD4 exome AF: 0.00000114 AC: 1AN: 875028Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 412072
GnomAD4 exome
AF:
AC:
1
AN:
875028
Hom.:
Cov.:
29
AF XY:
AC XY:
0
AN XY:
412072
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00000681 AC: 1AN: 146818Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 71428
GnomAD4 genome
?
AF:
AC:
1
AN:
146818
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
71428
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: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 05, 2023 | This sequence change affects the initiator methionine of the TNFRSF11A mRNA. The next in-frame methionine is located at codon 56. 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 variant has not been reported in the literature in individuals affected with TNFRSF11A-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
Polyphen
0.17
.;.;.;.;B
Vest4
0.76, 0.69, 0.77, 0.69
MutPred
Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);
MVP
0.99
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at