rs2228568

Positions:

• chr8-118926543-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002546.4(TNFRSF11B):​c.768A>G​(p.Leu256Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,613,968 control chromosomes in the GnomAD database, including 12,715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (866 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11849 hom.)
• Consequence: TNFRSF11B NM_002546.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.460

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 8-118926543-T-C is Benign according to our data. Variant chr8-118926543-T-C is described in ClinVar as [Benign]. Clinvar id is 258773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.768A>G	p.Leu256Leu	synonymous_variant	4/5	ENST00000297350.9	NP_002537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF11B	ENST00000297350.9	c.768A>G	p.Leu256Leu	synonymous_variant	4/5	1	NM_002546.4	ENSP00000297350.4
TNFRSF11B	ENST00000517352.1	n.*611A>G		non_coding_transcript_exon_variant	5/5	1		ENSP00000427924.1
TNFRSF11B	ENST00000517352.1	n.*611A>G		3_prime_UTR_variant	5/5	1		ENSP00000427924.1
TNFRSF11B	ENST00000521597.1	n.512A>G		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.0989 AC: 15049 AN: 152162 Hom.: 866 Cov.: 33

Gnomad AFR AF: 0.0557

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0763

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.00500

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0913

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.109

GnomAD3 exomes AF: 0.105 AC: 26430 AN: 251424 Hom.: 1736 AF XY: 0.110 AC XY: 14960 AN XY: 135888

Gnomad AFR exome AF: 0.0537

Gnomad AMR exome AF: 0.0498

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.00723

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.122 AC: 179032 AN: 1461688 Hom.: 11849 Cov.: 33 AF XY: 0.123 AC XY: 89597 AN XY: 727150

Gnomad4 AFR exome AF: 0.0558

Gnomad4 AMR exome AF: 0.0525

Gnomad4 ASJ exome AF: 0.142

Gnomad4 EAS exome AF: 0.00398

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.0989 AC: 15062 AN: 152280 Hom.: 866 Cov.: 33 AF XY: 0.0969 AC XY: 7215 AN XY: 74466

Gnomad4 AFR AF: 0.0558

Gnomad4 AMR AF: 0.0762

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.00501

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.0913

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.111

Alfa AF: 0.121 Hom.: 596

Bravo AF: 0.0920

Asia WGS AF: 0.0970 AC: 339 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.126

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hyperphosphatasemia with bone disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.46
CADD	Benign	7.8
DANN	Benign	0.79

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: rs2228568; hg19: chr8-119938782; COSMIC: COSV52071389;