chr13-42574305-T-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_003701.4(TNFSF11):c.2T>C(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 0.0000382 in 1,545,158 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 1 hom. )
Consequence
TNFSF11
NM_003701.4 start_lost
NM_003701.4 start_lost
Scores
6
5
4
Clinical Significance
Conservation
PhyloP100: 2.44
Genes affected
TNFSF11 (HGNC:11926): (TNF superfamily member 11) This gene encodes a member of the tumor necrosis factor (TNF) cytokine family which is a ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation. This protein was shown to be a dentritic cell survival factor and is involved in the regulation of T cell-dependent immune response. T cell activation was reported to induce expression of this gene and lead to an increase of osteoclastogenesis and bone loss. This protein was shown to activate antiapoptotic kinase AKT/PKB through a signaling complex involving SRC kinase and tumor necrosis factor receptor-associated factor (TRAF) 6, which indicated this protein may have a role in the regulation of cell apoptosis. Targeted disruption of the related gene in mice led to severe osteopetrosis and a lack of osteoclasts. The deficient mice exhibited defects in early differentiation of T and B lymphocytes, and failed to form lobulo-alveolar mammary structures during pregnancy. Two alternatively spliced transcript variants have been found. [provided by RefSeq, Jul 2008]
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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 |
---|---|---|---|---|---|---|---|
TNFSF11 | NM_003701.4 | c.2T>C | p.Met1? | start_lost | 1/5 | ENST00000398795.7 | |
TNFSF11 | NM_033012.4 | c.-1+2567T>C | intron_variant | ||||
TNFSF11 | XM_047430707.1 | c.-1+2567T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNFSF11 | ENST00000398795.7 | c.2T>C | p.Met1? | start_lost | 1/5 | 1 | NM_003701.4 | P1 | |
TNFSF11 | ENST00000358545.6 | c.-1+2567T>C | intron_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000199 AC: 3AN: 151052Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000764 AC: 11AN: 143984Hom.: 0 AF XY: 0.000116 AC XY: 9AN XY: 77878
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GnomAD4 exome AF: 0.0000402 AC: 56AN: 1394106Hom.: 1 Cov.: 32 AF XY: 0.0000611 AC XY: 42AN XY: 687716
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GnomAD4 genome ? AF: 0.0000199 AC: 3AN: 151052Hom.: 0 Cov.: 33 AF XY: 0.0000406 AC XY: 3AN XY: 73804
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive osteopetrosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 05, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D
PROVEAN
Benign
N
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
P
Vest4
MutPred
Gain of phosphorylation at M1 (P = 0.0019);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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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