8-118924430-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002546.4(TNFRSF11B):c.1150T>C(p.Leu384=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,614,076 control chromosomes in the GnomAD database, including 3,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (1708 hom., cov: 33)
  • Exomes 𝑓: 0.0086 (1511 hom.)
• Consequence: TNFRSF11B NM_002546.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.11

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 8-118924430-A-G is Benign according to our data. Variant chr8-118924430-A-G is described in ClinVar as [Benign]. Clinvar id is 361688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF11B	NM_002546.4	c.1150T>C	p.Leu384=	synonymous_variant	5/5	ENST00000297350.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF11B	ENST00000297350.9	c.1150T>C	p.Leu384=	synonymous_variant	5/5	1	NM_002546.4	P1
TNFRSF11B	ENST00000521597.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0814 AC: 12384 AN: 152110 Hom.: 1702 Cov.: 33

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.0630

GnomAD3 exomes AF: 0.0216 AC: 5419 AN: 251416 Hom.: 696 AF XY: 0.0159 AC XY: 2166 AN XY: 135878

Gnomad AFR exome AF: 0.285

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.00856 AC: 12516 AN: 1461848 Hom.: 1511 Cov.: 31 AF XY: 0.00754 AC XY: 5484 AN XY: 727224

Gnomad4 AFR exome AF: 0.289

Gnomad4 AMR exome AF: 0.0180

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000660

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0815 AC: 12412 AN: 152228 Hom.: 1708 Cov.: 33 AF XY: 0.0779 AC XY: 5800 AN XY: 74434

Gnomad4 AFR AF: 0.282

Gnomad4 AMR AF: 0.0326

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00126

Gnomad4 OTH AF: 0.0624

Alfa AF: 0.00988 Hom.: 163

Bravo AF: 0.0932

Asia WGS AF: 0.0120 AC: 44 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00166

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	8.1
Dann	Benign	0.67

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: rs1804854; hg19: chr8-119936669;