8-118948422-C-G

Variant names:

• chr8-118948422-C-G
• rs6469789
• NM_002546.4:c.30+3370G>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.30+3370G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 152,042 control chromosomes in the GnomAD database, including 36,179 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 0.67 (36179 hom., cov: 31)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.232
• 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: 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.911 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.30+3370G>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.30+3370G>C		intron	N/A	ENSP00000297350.4
	TNFRSF11B	ENST00000517352.1	TSL:1	n.30+3370G>C		intron	N/A	ENSP00000427924.1

Frequencies

GnomAD3 genomes AF: 0.670 AC: 101750 AN: 151924 Hom.: 36116 Cov.: 31

Gnomad AFR AF: 0.918

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.671

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.656

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

GnomAD4 genome AF: 0.670 AC: 101864 AN: 152042 Hom.: 36179 Cov.: 31 AF XY: 0.671 AC XY: 49888 AN XY: 74310

African (AFR) AF: 0.918 AC: 38126 AN: 41510

American (AMR) AF: 0.607 AC: 9265 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 2331 AN: 3468

East Asian (EAS) AF: 0.749 AC: 3872 AN: 5172

South Asian (SAS) AF: 0.670 AC: 3229 AN: 4822

European-Finnish (FIN) AF: 0.558 AC: 5881 AN: 10540

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.548 AC: 37226 AN: 67958

Other (OTH) AF: 0.661 AC: 1392 AN: 2106

Alfa AF: 0.441 Hom.: 1096

Bravo AF: 0.679

Asia WGS AF: 0.760 AC: 2643 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.1
DANN	Benign	0.56
PhyloP100		-0.23
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: rs6469789; hg19: chr8-119960661;