8-118938766-A-G

Variant names:

• chr8-118938766-A-G
• rs3102725
• NM_002546.4:c.31-5466T>C

Variant summary

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

The NM_002546.4(TNFRSF11B):​c.31-5466T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.934 in 152,248 control chromosomes in the GnomAD database, including 66,394 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 0.93 (66394 hom., cov: 32)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.120
• 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: 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.939 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.31-5466T>C		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.31-5466T>C		intron	N/A	ENSP00000297350.4
	TNFRSF11B	ENST00000517352.1	TSL:1	n.31-5466T>C		intron	N/A	ENSP00000427924.1

Frequencies

GnomAD3 genomes AF: 0.934 AC: 142030 AN: 152130 Hom.: 66336 Cov.: 32

Gnomad AFR AF: 0.927

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.889

Gnomad ASJ AF: 0.938

Gnomad EAS AF: 0.873

Gnomad SAS AF: 0.963

Gnomad FIN AF: 0.961

Gnomad MID AF: 0.905

Gnomad NFE AF: 0.944

Gnomad OTH AF: 0.949

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

GnomAD4 genome AF: 0.934 AC: 142145 AN: 152248 Hom.: 66394 Cov.: 32 AF XY: 0.933 AC XY: 69479 AN XY: 74448

African (AFR) AF: 0.927 AC: 38526 AN: 41538

American (AMR) AF: 0.889 AC: 13580 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.938 AC: 3258 AN: 3472

East Asian (EAS) AF: 0.873 AC: 4511 AN: 5166

South Asian (SAS) AF: 0.962 AC: 4644 AN: 4826

European-Finnish (FIN) AF: 0.961 AC: 10212 AN: 10622

Middle Eastern (MID) AF: 0.905 AC: 266 AN: 294

European-Non Finnish (NFE) AF: 0.944 AC: 64231 AN: 68024

Other (OTH) AF: 0.950 AC: 2008 AN: 2114

Alfa AF: 0.930 Hom.: 10930

Bravo AF: 0.928

Asia WGS AF: 0.935 AC: 3252 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.7
DANN	Benign	0.52
PhyloP100		-0.12
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: rs3102725; hg19: chr8-119951005;