chr13-42574306-G-A

Position:

• chr13-42574306-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_003701.4(TNFSF11):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNFSF11 NM_003701.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

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]

ACMG classification

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.3G>A	p.Met1?	start_lost	1/5	ENST00000398795.7
TNFSF11	NM_033012.4	c.-1+2568G>A		intron_variant
TNFSF11	XM_047430707.1	c.-1+2568G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFSF11	ENST00000398795.7	c.3G>A	p.Met1?	start_lost	1/5	1	NM_003701.4	P1
TNFSF11	ENST00000358545.6	c.-1+2568G>A		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1394264 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 687822

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 21, 2021

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with TNFSF11-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 ExAC database. This sequence change affects the initiator methionine of the TNFSF11 mRNA. The next in-frame methionine is located at codon 18. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.62	D
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-1.5	N
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.85	P
Vest4		0.83
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.0194);
MVP		0.95
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.85
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-43148442;