13-42574305-T-G

Position:

chr13-42574305-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_003701.4(TNFSF11):c.2T>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 0.0000239 in 1,545,158 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.000024 ( 0 hom. )

Consequence

TNFSF11
NM_003701.4 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O: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]

TNFSF11 links:

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
TNFSF11	NM_003701.4 linkuse as main transcript	c.2T>G	p.Met1?	start_lost	1/5	ENST00000398795.7
TNFSF11	NM_033012.4 linkuse as main transcript	c.-1+2567T>G		intron_variant
TNFSF11	XM_047430707.1 linkuse as main transcript	c.-1+2567T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFSF11	ENST00000398795.7 linkuse as main transcript	c.2T>G	p.Met1?	start_lost	1/5	1	NM_003701.4	P1	O14788-1
TNFSF11	ENST00000358545.6 linkuse as main transcript	c.-1+2567T>G		intron_variant		1			O14788-2

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

151052

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000443

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000556

AC:

AN:

143984

Hom.:

AF XY:

0.0000514

AC XY:

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:

0.0000884

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000244

AC:

AN:

1394106

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

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:

0.0000759

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000241

Gnomad4 OTH exome

AF:

0.0000347

GnomAD4 genome

AF:

0.0000199

AC:

AN:

151052

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73804

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000443

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000686

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000343

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 28, 2022

This sequence change affects the initiator methionine of the TNFSF11 mRNA. The next in-frame methionine is located at codon 18. This variant is present in population databases (rs201199211, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with TNFSF11-related conditions. ClinVar contains an entry for this variant (Variation ID: 1177514). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Autosomal recessive osteopetrosis 2

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 12-07-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.65

MutationTaster

Benign

1.0

D;D;D;D;D

PROVEAN

Benign

-0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.93

Vest4

0.84

MVP

0.96

ClinPred

0.86

GERP RS

3.1

Varity_R

0.93

gMVP

0.89

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over