rs17536328

Variant names:

• chr13-42568893-C-T
• rs17536328
• ENST00000358545.6:c.-160+2131C>T

Variant summary

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

The ENST00000358545.6(TNFSF11):​c.-160+2131C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 152,008 control chromosomes in the GnomAD database, including 10,991 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 0.36 (10991 hom., cov: 32)
• Consequence: TNFSF11 ENST00000358545.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242
• Publications: 19 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=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000358545.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF11	NM_033012.4		c.-160+2131C>T		intron	N/A	NP_143026.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF11	ENST00000358545.6	TSL:1	c.-160+2131C>T		intron	N/A	ENSP00000351347.2

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54695 AN: 151890 Hom.: 10993 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.368

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

GnomAD4 genome AF: 0.360 AC: 54694 AN: 152008 Hom.: 10991 Cov.: 32 AF XY: 0.364 AC XY: 27064 AN XY: 74300

African (AFR) AF: 0.180 AC: 7466 AN: 41438

American (AMR) AF: 0.363 AC: 5545 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1097 AN: 3470

East Asian (EAS) AF: 0.436 AC: 2261 AN: 5190

South Asian (SAS) AF: 0.349 AC: 1677 AN: 4812

European-Finnish (FIN) AF: 0.518 AC: 5464 AN: 10550

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.440 AC: 29898 AN: 67948

Other (OTH) AF: 0.366 AC: 770 AN: 2106

Alfa AF: 0.414 Hom.: 26086

Bravo AF: 0.342

Asia WGS AF: 0.358 AC: 1245 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	6.5
DANN	Benign	0.58
PhyloP100		0.24
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: rs17536328; hg19: chr13-43143029;