rs12585014

Variant names:

• chr13-42566423-G-A
• rs12585014
• ENST00000358545.6:c.-301-198G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000358545.6(TNFSF11):​c.-301-198G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 152,164 control chromosomes in the GnomAD database, including 2,636 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2636 hom., cov: 32)
• Consequence: TNFSF11 ENST00000358545.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.414
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive osteopetrosis 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• autosomal recessive osteopetrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF11	NM_033012.4	c.-301-198G>A		intron_variant	Intron 1 of 6		NP_143026.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF11	ENST00000358545.6	c.-301-198G>A		intron_variant	Intron 1 of 6	1		ENSP00000351347.2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27051 AN: 152046 Hom.: 2626 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.182

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.178 AC: 27077 AN: 152164 Hom.: 2636 Cov.: 32 AF XY: 0.177 AC XY: 13162 AN XY: 74390

African (AFR) AF: 0.143 AC: 5921 AN: 41508

American (AMR) AF: 0.298 AC: 4553 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3470

East Asian (EAS) AF: 0.310 AC: 1606 AN: 5178

South Asian (SAS) AF: 0.119 AC: 573 AN: 4826

European-Finnish (FIN) AF: 0.129 AC: 1368 AN: 10590

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11819 AN: 67998

Other (OTH) AF: 0.180 AC: 380 AN: 2110

Alfa AF: 0.185 Hom.: 892

Bravo AF: 0.194

Asia WGS AF: 0.208 AC: 724 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.9
DANN	Benign	0.57
PhyloP100		-0.41
PromoterAI		0.0037	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12585014; hg19: chr13-43140559;