8-118932927-G-A

Position:

• chr8-118932927-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002546.4(TNFRSF11B):​c.400+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,613,884 control chromosomes in the GnomAD database, including 12,614 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (865 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11749 hom.)
• Consequence: TNFRSF11B NM_002546.4 splice_region, intron
• Scores: Splicing: ADA: 0.0004132
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.80

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 8-118932927-G-A is Benign according to our data. Variant chr8-118932927-G-A is described in ClinVar as [Benign]. Clinvar id is 258772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.400+4C>T		splice_region_variant, intron_variant		ENST00000297350.9	NP_002537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF11B	ENST00000297350.9	c.400+4C>T		splice_region_variant, intron_variant		1	NM_002546.4	ENSP00000297350.4
TNFRSF11B	ENST00000517352.1	n.400+4C>T		splice_region_variant, intron_variant		1		ENSP00000427924.1

Frequencies

GnomAD3 genomes AF: 0.0986 AC: 15001 AN: 152086 Hom.: 865 Cov.: 32

Gnomad AFR AF: 0.0560

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0761

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.0918

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.105 AC: 26347 AN: 250686 Hom.: 1719 AF XY: 0.110 AC XY: 14951 AN XY: 135682

Gnomad AFR exome AF: 0.0531

Gnomad AMR exome AF: 0.0495

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.00734

Gnomad SAS exome AF: 0.142

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.122 AC: 178393 AN: 1461680 Hom.: 11749 Cov.: 32 AF XY: 0.123 AC XY: 89342 AN XY: 727154

Gnomad4 AFR exome AF: 0.0558

Gnomad4 AMR exome AF: 0.0523

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.00403

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.0986 AC: 15014 AN: 152204 Hom.: 865 Cov.: 32 AF XY: 0.0968 AC XY: 7204 AN XY: 74416

Gnomad4 AFR AF: 0.0561

Gnomad4 AMR AF: 0.0760

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.00483

Gnomad4 SAS AF: 0.139

Gnomad4 FIN AF: 0.0918

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.109

Alfa AF: 0.122 Hom.: 1898

Bravo AF: 0.0916

Asia WGS AF: 0.0960 AC: 336 AN: 3478

EpiCase AF: 0.127

EpiControl AF: 0.124

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.035
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.038
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: rs1564858; hg19: chr8-119945166;