rs10955912

Variant names:

• chr8-118936301-T-C
• rs10955912
• NM_002546.4:c.31-3001A>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.31-3001A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 152,102 control chromosomes in the GnomAD database, including 5,350 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 0.25 (5350 hom., cov: 32)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.696
• Publications: 6 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.38 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.31-3001A>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.31-3001A>G		intron	N/A	ENSP00000297350.4	O00300
	TNFRSF11B	ENST00000517352.1	TSL:1	n.31-3001A>G		intron	N/A	ENSP00000427924.1	E5RFV7
	TNFRSF11B	ENST00000966249.1		c.159+366A>G		intron	N/A	ENSP00000636308.1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38242 AN: 151984 Hom.: 5332 Cov.: 32

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.257

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

GnomAD4 genome AF: 0.252 AC: 38300 AN: 152102 Hom.: 5350 Cov.: 32 AF XY: 0.248 AC XY: 18478 AN XY: 74360

African (AFR) AF: 0.385 AC: 15968 AN: 41462

American (AMR) AF: 0.213 AC: 3255 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 820 AN: 3468

East Asian (EAS) AF: 0.137 AC: 709 AN: 5182

South Asian (SAS) AF: 0.212 AC: 1019 AN: 4812

European-Finnish (FIN) AF: 0.182 AC: 1925 AN: 10584

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13835 AN: 67988

Other (OTH) AF: 0.263 AC: 556 AN: 2112

Alfa AF: 0.230 Hom.: 535

Bravo AF: 0.259

Asia WGS AF: 0.212 AC: 738 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.3
DANN	Benign	0.46
PhyloP100		0.70
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: rs10955912; hg19: chr8-119948540;