8-118923829-A-G

Position:

• chr8-118923829-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002546.4(TNFRSF11B):​c.*545T>C variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00732 in 152,720 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0073 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (0 hom.)
• Consequence: TNFRSF11B NM_002546.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.86

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 8-118923829-A-G is Benign according to our data. Variant chr8-118923829-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 361684.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00733 (1115/152218) while in subpopulation AMR AF= 0.0183 (279/15286). AF 95% confidence interval is 0.0165. There are 5 homozygotes in gnomad4. There are 568 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF11B	NM_002546.4	c.*545T>C		3_prime_UTR_variant	5/5	ENST00000297350.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF11B	ENST00000297350.9	c.*545T>C		3_prime_UTR_variant	5/5	1	NM_002546.4	P1

Frequencies

GnomAD3 genomes AF: 0.00733 AC: 1115 AN: 152100 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00359

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00959

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.00598 AC: 3 AN: 502 Hom.: 0 Cov.: 0 AF XY: 0.00671 AC XY: 2 AN XY: 298

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00266

Gnomad4 NFE exome AF: 0.0192

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00733 AC: 1115 AN: 152218 Hom.: 5 Cov.: 33 AF XY: 0.00763 AC XY: 568 AN XY: 74440

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00359

Gnomad4 NFE AF: 0.00959

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00243 Hom.: 0

Bravo AF: 0.00894

Asia WGS AF: 0.000884 AC: 3 AN: 3408

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperphosphatasemia with bone disease Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.56

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: rs11573947; hg19: chr8-119936068;