8-118939534-G-A

Variant names:

• chr8-118939534-G-A
• rs1032128
• NM_002546.4:c.31-6234C>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.31-6234C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 152,012 control chromosomes in the GnomAD database, including 7,567 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 0.31 (7567 hom., cov: 32)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.368
• Publications: 20 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.592 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.31-6234C>T		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.31-6234C>T		intron	N/A	ENSP00000297350.4
	TNFRSF11B	ENST00000517352.1	TSL:1	n.31-6234C>T		intron	N/A	ENSP00000427924.1
	TNFRSF11B	ENST00000966249.1		c.31-2739C>T		intron	N/A	ENSP00000636308.1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46641 AN: 151896 Hom.: 7563 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.285

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

GnomAD4 genome AF: 0.307 AC: 46665 AN: 152012 Hom.: 7567 Cov.: 32 AF XY: 0.317 AC XY: 23530 AN XY: 74298

African (AFR) AF: 0.312 AC: 12924 AN: 41470

American (AMR) AF: 0.322 AC: 4925 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1093 AN: 3472

East Asian (EAS) AF: 0.610 AC: 3143 AN: 5152

South Asian (SAS) AF: 0.371 AC: 1783 AN: 4810

European-Finnish (FIN) AF: 0.369 AC: 3892 AN: 10558

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18042 AN: 67954

Other (OTH) AF: 0.282 AC: 595 AN: 2110

Alfa AF: 0.278 Hom.: 17343

Bravo AF: 0.302

Asia WGS AF: 0.464 AC: 1614 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.7
DANN	Benign	0.51
PhyloP100		0.37
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: rs1032128; hg19: chr8-119951773;