8-118938429-C-T

Variant names:

• chr8-118938429-C-T
• rs1485286
• NM_002546.4:c.31-5129G>A

Variant summary

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

The NM_002546.4(TNFRSF11B):​c.31-5129G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 152,106 control chromosomes in the GnomAD database, including 37,183 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 0.70 (37183 hom., cov: 33)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.214
• Publications: 13 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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.31-5129G>A		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.31-5129G>A		intron_variant	Intron 1 of 4	1	NM_002546.4	ENSP00000297350.4
TNFRSF11B	ENST00000517352.1	n.31-5129G>A		intron_variant	Intron 1 of 4	1		ENSP00000427924.1

Frequencies

GnomAD3 genomes AF: 0.696 AC: 105804 AN: 151988 Hom.: 37145 Cov.: 33

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.832

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.682

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.664

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.735

Gnomad OTH AF: 0.717

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

GnomAD4 genome AF: 0.696 AC: 105896 AN: 152106 Hom.: 37183 Cov.: 33 AF XY: 0.688 AC XY: 51141 AN XY: 74340

African (AFR) AF: 0.688 AC: 28546 AN: 41492

American (AMR) AF: 0.681 AC: 10412 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 2366 AN: 3470

East Asian (EAS) AF: 0.389 AC: 2014 AN: 5174

South Asian (SAS) AF: 0.643 AC: 3097 AN: 4814

European-Finnish (FIN) AF: 0.664 AC: 7011 AN: 10558

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.735 AC: 49983 AN: 67990

Other (OTH) AF: 0.720 AC: 1515 AN: 2104

Alfa AF: 0.714 Hom.: 52866

Bravo AF: 0.698

Asia WGS AF: 0.540 AC: 1880 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.7
DANN	Benign	0.54
PhyloP100		-0.21
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: rs1485286; hg19: chr8-119950668;