8-118933902-T-C

Variant names:

• chr8-118933902-T-C
• rs3134053
• NM_002546.4:c.31-602A>G

Variant summary

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

The NM_002546.4(TNFRSF11B):​c.31-602A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.895 in 152,226 control chromosomes in the GnomAD database, including 61,114 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 0.89 (61114 hom., cov: 32)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.86
• Publications: 7 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.918 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.31-602A>G		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.31-602A>G		intron	N/A	ENSP00000297350.4	O00300
	TNFRSF11B	ENST00000517352.1	TSL:1	n.31-602A>G		intron	N/A	ENSP00000427924.1	E5RFV7
	TNFRSF11B	ENST00000966249.1		c.160-602A>G		intron	N/A	ENSP00000636308.1

Frequencies

GnomAD3 genomes AF: 0.895 AC: 136128 AN: 152108 Hom.: 61072 Cov.: 32

Gnomad AFR AF: 0.876

Gnomad AMI AF: 0.976

Gnomad AMR AF: 0.841

Gnomad ASJ AF: 0.925

Gnomad EAS AF: 0.709

Gnomad SAS AF: 0.914

Gnomad FIN AF: 0.922

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.924

Gnomad OTH AF: 0.912

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

GnomAD4 genome AF: 0.895 AC: 136224 AN: 152226 Hom.: 61114 Cov.: 32 AF XY: 0.893 AC XY: 66436 AN XY: 74408

African (AFR) AF: 0.876 AC: 36396 AN: 41542

American (AMR) AF: 0.840 AC: 12846 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.925 AC: 3211 AN: 3472

East Asian (EAS) AF: 0.709 AC: 3659 AN: 5162

South Asian (SAS) AF: 0.913 AC: 4397 AN: 4814

European-Finnish (FIN) AF: 0.922 AC: 9776 AN: 10604

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.924 AC: 62855 AN: 68026

Other (OTH) AF: 0.914 AC: 1930 AN: 2112

Alfa AF: 0.908 Hom.: 8106

Bravo AF: 0.889

Asia WGS AF: 0.809 AC: 2816 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.039
DANN	Benign	0.45
PhyloP100		-4.9
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: rs3134053; hg19: chr8-119946141;