rs2228568

Variant names:

• chr8-118926543-T-C
• rs2228568
• NM_002546.4:c.768A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11B	NM_002546.4	MANE Select	c.768A>G	p.Leu256Leu	synonymous	Exon 4 of 5	NP_002537.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11B	ENST00000297350.9	TSL:1 MANE Select	c.768A>G	p.Leu256Leu	synonymous	Exon 4 of 5	ENSP00000297350.4	O00300
	TNFRSF11B	ENST00000517352.1	TSL:1	n.*611A>G		non_coding_transcript_exon	Exon 5 of 5	ENSP00000427924.1	E5RFV7
	TNFRSF11B	ENST00000517352.1	TSL:1	n.*611A>G		3_prime_UTR	Exon 5 of 5	ENSP00000427924.1	E5RFV7

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

GnomAD2 exomes AF: 0.105 AC: 26430 AN: 251424 AF XY: 0.110

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 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

African (AFR) AF: 0.0558 AC: 1868 AN: 33476

American (AMR) AF: 0.0525 AC: 2348 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3699 AN: 26132

East Asian (EAS) AF: 0.00398 AC: 158 AN: 39692

South Asian (SAS) AF: 0.137 AC: 11840 AN: 86254

European-Finnish (FIN) AF: 0.101 AC: 5417 AN: 53378

Middle Eastern (MID) AF: 0.112 AC: 647 AN: 5766

European-Non Finnish (NFE) AF: 0.131 AC: 145733 AN: 1111882

Other (OTH) AF: 0.121 AC: 7322 AN: 60388

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

African (AFR) AF: 0.0558 AC: 2318 AN: 41552

American (AMR) AF: 0.0762 AC: 1165 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 464 AN: 3460

East Asian (EAS) AF: 0.00501 AC: 26 AN: 5192

South Asian (SAS) AF: 0.138 AC: 666 AN: 4824

European-Finnish (FIN) AF: 0.0913 AC: 969 AN: 10614

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9095 AN: 68022

Other (OTH) AF: 0.111 AC: 234 AN: 2114

Alfa AF: 0.121 Hom.: 597

Bravo AF: 0.0920

Asia WGS AF: 0.0970 AC: 339 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.126

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hyperphosphatasemia with bone disease (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.8
DANN	Benign	0.79
PhyloP100		0.46
Mutation Taster		=98/2	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: rs2228568; hg19: chr8-119938782; COSMIC: COSV52071389;