8-118942872-G-A

Variant names:

• chr8-118942872-G-A
• rs6415470
• NM_002546.4:c.30+8920C>T

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+8920C>T 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 151,922 control chromosomes in the GnomAD database, including 36,015 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 (36015 hom., cov: 30)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.546
• Publications: 8 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.30+8920C>T		intron_variant	Intron 1 of 4	ENST00000297350.9	NP_002537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11B	ENST00000297350.9	c.30+8920C>T		intron_variant	Intron 1 of 4	1	NM_002546.4	ENSP00000297350.4
TNFRSF11B	ENST00000517352.1	n.30+8920C>T		intron_variant	Intron 1 of 4	1		ENSP00000427924.1

Frequencies

GnomAD3 genomes AF: 0.669 AC: 101512 AN: 151804 Hom.: 35952 Cov.: 30

Gnomad AFR AF: 0.916

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.670

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.547

Gnomad OTH AF: 0.653

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

GnomAD4 genome AF: 0.669 AC: 101626 AN: 151922 Hom.: 36015 Cov.: 30 AF XY: 0.670 AC XY: 49787 AN XY: 74262

African (AFR) AF: 0.916 AC: 37979 AN: 41472

American (AMR) AF: 0.606 AC: 9249 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2331 AN: 3466

East Asian (EAS) AF: 0.749 AC: 3862 AN: 5156

South Asian (SAS) AF: 0.669 AC: 3223 AN: 4816

European-Finnish (FIN) AF: 0.559 AC: 5887 AN: 10536

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.547 AC: 37173 AN: 67908

Other (OTH) AF: 0.658 AC: 1383 AN: 2102

Alfa AF: 0.648 Hom.: 4849

Bravo AF: 0.678

Asia WGS AF: 0.759 AC: 2641 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.064
DANN	Benign	0.35
PhyloP100		-0.55
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: rs6415470; hg19: chr8-119955111; COSMIC: COSV52074714;