NM_002546.4:c.31-4229T>C

Variant names:

• chr8-118937529-A-G
• rs2875845
• NM_002546.4:c.31-4229T>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.31-4229T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,276 control chromosomes in the GnomAD database, including 1,658 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 0.14 (1658 hom., cov: 33)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.132
• Publications: 10 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 (SAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.31-4229T>C		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.31-4229T>C		intron_variant	Intron 1 of 4	1	NM_002546.4	ENSP00000297350.4
TNFRSF11B	ENST00000517352.1	n.31-4229T>C		intron_variant	Intron 1 of 4	1		ENSP00000427924.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21677 AN: 152158 Hom.: 1653 Cov.: 33

Gnomad AFR AF: 0.0940

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.171

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

GnomAD4 genome AF: 0.142 AC: 21689 AN: 152276 Hom.: 1658 Cov.: 33 AF XY: 0.143 AC XY: 10641 AN XY: 74456

African (AFR) AF: 0.0938 AC: 3899 AN: 41558

American (AMR) AF: 0.155 AC: 2378 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 699 AN: 3472

East Asian (EAS) AF: 0.136 AC: 708 AN: 5188

South Asian (SAS) AF: 0.182 AC: 880 AN: 4822

European-Finnish (FIN) AF: 0.155 AC: 1639 AN: 10608

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10908 AN: 68014

Other (OTH) AF: 0.178 AC: 375 AN: 2108

Alfa AF: 0.161 Hom.: 3501

Bravo AF: 0.141

Asia WGS AF: 0.182 AC: 632 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	1.5
DANN	Benign	0.75
PhyloP100		-0.13
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: rs2875845; hg19: chr8-119949768;