rs2228568

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.460

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4 link	c.768A>G	p.Leu256Leu	synonymous_variant	Exon 4 of 5	ENST00000297350.9	NP_002537.3	O00300

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNFRSF11B	ENST00000297350.9 link	c.768A>G	p.Leu256Leu	synonymous_variant	Exon 4 of 5	1	NM_002546.4	ENSP00000297350.4	O00300
TNFRSF11B	ENST00000517352.1 link	n.*611A>G		non_coding_transcript_exon_variant	Exon 5 of 5	1		ENSP00000427924.1	E5RFV7
TNFRSF11B	ENST00000517352.1 link	n.*611A>G		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000427924.1	E5RFV7
TNFRSF11B	ENST00000521597.1 link	n.512A>G		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0989

AC:

15049

AN:

152162

Hom.:

866

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.123

AC XY:

89597

AN XY:

727150

show subpopulations

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.:

AF XY:

0.0969

AC XY:

7215

AN XY:

74466

show subpopulations

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperphosphatasemia with bone disease

Benign:1

Jan 12, 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

-0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over