rs3134058

Variant names:

• chr8-118941869-G-A
• rs3134058
• NM_002546.4:c.31-8569C>T

Variant summary

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

The NM_002546.4(TNFRSF11B):​c.31-8569C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 151,842 control chromosomes in the GnomAD database, including 20,514 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 0.50 (20514 hom., cov: 31)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0150
• Publications: 15 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.69 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11B	NM_002546.4	MANE Select	c.31-8569C>T		intron	N/A	NP_002537.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11B	ENST00000297350.9	TSL:1 MANE Select	c.31-8569C>T		intron	N/A	ENSP00000297350.4
	TNFRSF11B	ENST00000517352.1	TSL:1	n.31-8569C>T		intron	N/A	ENSP00000427924.1

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76390 AN: 151724 Hom.: 20473 Cov.: 31

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.459

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.507

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

GnomAD4 genome AF: 0.504 AC: 76479 AN: 151842 Hom.: 20514 Cov.: 31 AF XY: 0.507 AC XY: 37623 AN XY: 74186

African (AFR) AF: 0.697 AC: 28865 AN: 41404

American (AMR) AF: 0.426 AC: 6501 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1694 AN: 3460

East Asian (EAS) AF: 0.614 AC: 3167 AN: 5154

South Asian (SAS) AF: 0.536 AC: 2578 AN: 4806

European-Finnish (FIN) AF: 0.459 AC: 4830 AN: 10534

Middle Eastern (MID) AF: 0.572 AC: 167 AN: 292

European-Non Finnish (NFE) AF: 0.402 AC: 27333 AN: 67918

Other (OTH) AF: 0.510 AC: 1073 AN: 2102

Alfa AF: 0.432 Hom.: 26894

Bravo AF: 0.507

Asia WGS AF: 0.609 AC: 2117 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.2
DANN	Benign	0.75
PhyloP100		0.015
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: rs3134058; hg19: chr8-119954108;