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GeneBe

13-42574305-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

Scores

6
5
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.44
Variant links:
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
TNFSF11NM_003701.4 linkuse as main transcriptc.2T>C p.Met1? start_lost 1/5 ENST00000398795.7
TNFSF11NM_033012.4 linkuse as main transcriptc.-1+2567T>C intron_variant
TNFSF11XM_047430707.1 linkuse as main transcriptc.-1+2567T>C intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TNFSF11ENST00000398795.7 linkuse as main transcriptc.2T>C p.Met1? start_lost 1/51 NM_003701.4 P1O14788-1
TNFSF11ENST00000358545.6 linkuse as main transcriptc.-1+2567T>C intron_variant 1 O14788-2

Frequencies

GnomAD3 genomes
AF:
0.0000199
AC:
3
AN:
151052
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000244
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000419
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000764
AC:
11
AN:
143984
Hom.:
0
AF XY:
0.000116
AC XY:
9
AN XY:
77878
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:
0.000486
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000402
AC:
56
AN:
1394106
Hom.:
1
Cov.:
32
AF XY:
0.0000611
AC XY:
42
AN XY:
687716
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:
0.000645
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000464
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000199
AC:
3
AN:
151052
Hom.:
0
Cov.:
33
AF XY:
0.0000406
AC XY:
3
AN XY:
73804
show subpopulations
Gnomad4 AFR
AF:
0.0000244
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000419
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000171
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000686
AC:
6

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 submitterclinical testingRevvity Omics, RevvityJul 05, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.21
Cadd
Uncertain
25
Dann
Uncertain
0.99
DEOGEN2
Benign
0.32
T
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Benign
0.62
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.99
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Uncertain
0.57
D
MutationTaster
Benign
1.0
D;D;D;D;D
PROVEAN
Benign
-0.65
N
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.93
P
Vest4
0.84
MutPred
0.97
Gain of phosphorylation at M1 (P = 0.0019);
MVP
0.96
ClinPred
0.58
D
GERP RS
3.1
Varity_R
0.83
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs201199211; hg19: chr13-43148441; API