rs3102734

Positions:

• chr8-118951777-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.30+15C>T		intron_variant		ENST00000297350.9	NP_002537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF11B	ENST00000297350.9	c.30+15C>T		intron_variant		1	NM_002546.4	ENSP00000297350	P1
TNFRSF11B	ENST00000517352.1	c.30+15C>T		intron_variant, NMD_transcript_variant		1		ENSP00000427924

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

GnomAD3 exomes AF: 0.0726 AC: 14531 AN: 200110 Hom.: 724 AF XY: 0.0668 AC XY: 7237 AN XY: 108342

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 SAS exome AF: 0.0339

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

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.0607

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.0361

Gnomad4 FIN exome AF: 0.0373

Gnomad4 NFE exome AF: 0.0524

Gnomad4 OTH exome AF: 0.0646

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

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.0614

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.0384

Gnomad4 FIN AF: 0.0386

Gnomad4 NFE AF: 0.0560

Gnomad4 OTH AF: 0.0663

Alfa AF: 0.0754 Hom.: 132

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Hyperphosphatasemia with bone disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs3102734; hg19: chr8-119964016;