rs3102734

Variant names:

• chr8-118951777-G-A
• rs3102734
• NM_002546.4:c.30+15C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002546.4(TNFRSF11B):​c.30+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0616 in 1,585,750 control chromosomes in the GnomAD database, including 3,784 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (834 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2950 hom.)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.205
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 8-118951777-G-A is Benign according to our data. Variant chr8-118951777-G-A is described in ClinVar as Benign. ClinVar VariationId is 361696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.30+15C>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+15C>T		intron_variant	Intron 1 of 4	1	NM_002546.4	ENSP00000297350.4
TNFRSF11B	ENST00000517352.1	n.30+15C>T		intron_variant	Intron 1 of 4	1		ENSP00000427924.1

Frequencies

GnomAD3 genomes AF: 0.0936 AC: 14236 AN: 152096 Hom.: 826 Cov.: 33

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0614

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.0387

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0560

Gnomad OTH AF: 0.0675

GnomAD2 exomes AF: 0.0726 AC: 14531 AN: 200110 AF XY: 0.0668

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.0616

Gnomad EAS exome AF: 0.126

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.0513

Gnomad OTH exome AF: 0.0669

GnomAD4 exome AF: 0.0582 AC: 83398 AN: 1433538 Hom.: 2950 Cov.: 30 AF XY: 0.0572 AC XY: 40650 AN XY: 710284

African (AFR) AF: 0.168 AC: 5511 AN: 32752

American (AMR) AF: 0.126 AC: 5219 AN: 41274

Ashkenazi Jewish (ASJ) AF: 0.0607 AC: 1555 AN: 25604

East Asian (EAS) AF: 0.120 AC: 4545 AN: 38018

South Asian (SAS) AF: 0.0361 AC: 2958 AN: 81968

European-Finnish (FIN) AF: 0.0373 AC: 1900 AN: 50888

Middle Eastern (MID) AF: 0.0579 AC: 332 AN: 5738

European-Non Finnish (NFE) AF: 0.0524 AC: 57550 AN: 1097996

Other (OTH) AF: 0.0646 AC: 3828 AN: 59300

GnomAD4 genome AF: 0.0936 AC: 14252 AN: 152212 Hom.: 834 Cov.: 33 AF XY: 0.0925 AC XY: 6887 AN XY: 74416

African (AFR) AF: 0.167 AC: 6945 AN: 41516

American (AMR) AF: 0.122 AC: 1861 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0614 AC: 213 AN: 3470

East Asian (EAS) AF: 0.128 AC: 658 AN: 5156

South Asian (SAS) AF: 0.0384 AC: 185 AN: 4822

European-Finnish (FIN) AF: 0.0386 AC: 410 AN: 10616

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0560 AC: 3809 AN: 68012

Other (OTH) AF: 0.0663 AC: 140 AN: 2112

Alfa AF: 0.0745 Hom.: 205

Bravo AF: 0.103

Asia WGS AF: 0.0730 AC: 256 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperphosphatasemia with bone disease Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.89
PhyloP100		-0.20
PromoterAI		0.019	Neutral
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: rs3102734; hg19: chr8-119964016; COSMIC: COSV107386741;