13-42574319-A-G

Position:

• chr13-42574319-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003701.4(TNFSF11):​c.16A>G​(p.Arg6Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TNFSF11 NM_003701.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.648

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38000974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFSF11	NM_003701.4	c.16A>G	p.Arg6Gly	missense_variant	1/5	ENST00000398795.7	NP_003692.1
TNFSF11	NM_033012.4	c.-1+2581A>G		intron_variant			NP_143026.1
TNFSF11	XM_047430707.1	c.-1+2581A>G		intron_variant			XP_047286663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFSF11	ENST00000398795.7	c.16A>G	p.Arg6Gly	missense_variant	1/5	1	NM_003701.4	ENSP00000381775	P1
TNFSF11	ENST00000358545.6	c.-1+2581A>G		intron_variant		1		ENSP00000351347

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000689 AC: 1 AN: 145148 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 78508

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: 0.0000442

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394536 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 687986

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: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000110 AC: 1

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 12, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 6 of the TNFSF11 protein (p.Arg6Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.070
Eigen_PC	Benign	0.017
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.52	D;D;D;D;D
PrimateAI	Pathogenic	0.94	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.32
MutPred		0.24		Gain of catalytic residue at K10 (P = 0.0205);
MVP		0.51
ClinPred		0.58	D
GERP RS		2.7
Varity_R		0.13
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs775270513; hg19: chr13-43148455;