rs6469783

Variant names:

• chr8-118927026-C-T
• rs6469783
• NM_002546.4:c.593-308G>A

Variant summary

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

The NM_002546.4(TNFRSF11B):​c.593-308G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 152,050 control chromosomes in the GnomAD database, including 5,584 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 0.22 (5584 hom., cov: 32)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.426
• Publications: 5 publications found

Genes affected

TNFRSF11B (HGNC:11909): (TNF receptor superfamily member 11b) The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein is an osteoblast-secreted decoy receptor that functions as a negative regulator of bone resorption. This protein specifically binds to its ligand, osteoprotegerin ligand, both of which are key extracellular regulators of osteoclast development. Studies of the mouse counterpart also suggest that this protein and its ligand play a role in lymph-node organogenesis and vascular calcification. Alternatively spliced transcript variants of this gene have been reported, but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

TNFRSF11B Gene-Disease associations (from GenCC):

• juvenile Paget disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002546.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11B	NM_002546.4	MANE Select	c.593-308G>A		intron	N/A	NP_002537.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11B	ENST00000297350.9	TSL:1 MANE Select	c.593-308G>A		intron	N/A	ENSP00000297350.4	O00300
	TNFRSF11B	ENST00000517352.1	TSL:1	n.*436-308G>A		intron	N/A	ENSP00000427924.1	E5RFV7
	TNFRSF11B	ENST00000966249.1		c.722-308G>A		intron	N/A	ENSP00000636308.1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33242 AN: 151932 Hom.: 5557 Cov.: 32

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.00500

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.0912

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.195

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

GnomAD4 genome AF: 0.219 AC: 33314 AN: 152050 Hom.: 5584 Cov.: 32 AF XY: 0.213 AC XY: 15844 AN XY: 74322

African (AFR) AF: 0.471 AC: 19508 AN: 41434

American (AMR) AF: 0.127 AC: 1934 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 468 AN: 3470

East Asian (EAS) AF: 0.00501 AC: 26 AN: 5186

South Asian (SAS) AF: 0.140 AC: 673 AN: 4822

European-Finnish (FIN) AF: 0.0912 AC: 964 AN: 10570

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9195 AN: 67986

Other (OTH) AF: 0.196 AC: 413 AN: 2110

Alfa AF: 0.195 Hom.: 534

Bravo AF: 0.230

Asia WGS AF: 0.117 AC: 407 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.5
DANN	Benign	0.50
PhyloP100		0.43
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: rs6469783; hg19: chr8-119939265;