NM_002546.4:c.31-1268C>T

Variant names:

• chr8-118934568-G-A
• rs3102724
• NM_002546.4:c.31-1268C>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.31-1268C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 151,834 control chromosomes in the GnomAD database, including 13,119 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 0.41 (13119 hom., cov: 31)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0160
• Publications: 18 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.31-1268C>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.31-1268C>T		intron_variant	Intron 1 of 4	1	NM_002546.4	ENSP00000297350.4
TNFRSF11B	ENST00000517352.1	n.31-1268C>T		intron_variant	Intron 1 of 4	1		ENSP00000427924.1

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61710 AN: 151716 Hom.: 13096 Cov.: 31

Gnomad AFR AF: 0.533

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.415

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

GnomAD4 genome AF: 0.407 AC: 61767 AN: 151834 Hom.: 13119 Cov.: 31 AF XY: 0.410 AC XY: 30415 AN XY: 74178

African (AFR) AF: 0.533 AC: 22050 AN: 41372

American (AMR) AF: 0.342 AC: 5219 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1530 AN: 3468

East Asian (EAS) AF: 0.448 AC: 2306 AN: 5148

South Asian (SAS) AF: 0.463 AC: 2229 AN: 4810

European-Finnish (FIN) AF: 0.391 AC: 4119 AN: 10534

Middle Eastern (MID) AF: 0.534 AC: 156 AN: 292

European-Non Finnish (NFE) AF: 0.339 AC: 23021 AN: 67926

Other (OTH) AF: 0.420 AC: 887 AN: 2112

Alfa AF: 0.364 Hom.: 45341

Bravo AF: 0.409

Asia WGS AF: 0.467 AC: 1625 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.51
PhyloP100		-0.016
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: rs3102724; hg19: chr8-119946807;