rs922996

Variant names:

• chr13-42604535-G-A
• rs922996
• NM_003701.4:c.533-1962G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-42604535-G-A
• chr13-42604535-G-T

Variant summary

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

The NM_003701.4(TNFSF11):​c.533-1962G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 151,916 control chromosomes in the GnomAD database, including 17,853 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 0.48 (17853 hom., cov: 31)
• Consequence: TNFSF11 NM_003701.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.175
• Publications: 7 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.545 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003701.4. 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_003701.4	MANE Select	c.533-1962G>A		intron	N/A	NP_003692.1
	TNFSF11	NM_033012.4		c.314-1962G>A		intron	N/A	NP_143026.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF11	ENST00000398795.7	TSL:1 MANE Select	c.533-1962G>A		intron	N/A	ENSP00000381775.3
	TNFSF11	ENST00000358545.6	TSL:1	c.314-1962G>A		intron	N/A	ENSP00000351347.2

Frequencies

GnomAD3 genomes AF: 0.481 AC: 72977 AN: 151800 Hom.: 17834 Cov.: 31

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.506

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

GnomAD4 genome AF: 0.481 AC: 73031 AN: 151916 Hom.: 17853 Cov.: 31 AF XY: 0.480 AC XY: 35613 AN XY: 74266

African (AFR) AF: 0.438 AC: 18146 AN: 41416

American (AMR) AF: 0.547 AC: 8345 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2335 AN: 3468

East Asian (EAS) AF: 0.507 AC: 2614 AN: 5160

South Asian (SAS) AF: 0.563 AC: 2704 AN: 4804

European-Finnish (FIN) AF: 0.410 AC: 4323 AN: 10544

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.483 AC: 32825 AN: 67940

Other (OTH) AF: 0.509 AC: 1075 AN: 2112

Alfa AF: 0.478 Hom.: 2949

Bravo AF: 0.490

Asia WGS AF: 0.546 AC: 1898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.44
DANN	Benign	0.40
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs922996; hg19: chr13-43178671;