8-118947384-T-C

Variant names:

• chr8-118947384-T-C
• rs11573829
• NM_002546.4:c.30+4408A>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.30+4408A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 152,048 control chromosomes in the GnomAD database, including 36,051 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 (36051 hom., cov: 32)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.448
• Publications: 12 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.908 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+4408A>G		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+4408A>G		intron	N/A	ENSP00000297350.4
	TNFRSF11B	ENST00000517352.1	TSL:1	n.30+4408A>G		intron	N/A	ENSP00000427924.1

Frequencies

GnomAD3 genomes AF: 0.669 AC: 101590 AN: 151930 Hom.: 35988 Cov.: 32

Gnomad AFR AF: 0.916

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.670

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.547

Gnomad OTH AF: 0.655

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

GnomAD4 genome AF: 0.669 AC: 101704 AN: 152048 Hom.: 36051 Cov.: 32 AF XY: 0.670 AC XY: 49806 AN XY: 74300

African (AFR) AF: 0.916 AC: 38024 AN: 41522

American (AMR) AF: 0.607 AC: 9269 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 2332 AN: 3472

East Asian (EAS) AF: 0.749 AC: 3860 AN: 5154

South Asian (SAS) AF: 0.669 AC: 3226 AN: 4820

European-Finnish (FIN) AF: 0.557 AC: 5877 AN: 10548

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

European-Non Finnish (NFE) AF: 0.547 AC: 37180 AN: 67936

Other (OTH) AF: 0.660 AC: 1395 AN: 2114

Alfa AF: 0.569 Hom.: 8982

Bravo AF: 0.678

Asia WGS AF: 0.760 AC: 2641 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.4
DANN	Benign	0.50
PhyloP100		-0.45
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: rs11573829; hg19: chr8-119959623;