rs7844539

Variant names:

• chr8-118926486-T-G
• rs7844539
• NM_002546.4:c.817+8A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002546.4(TNFRSF11B):​c.817+8A>C 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 1,602,938 control chromosomes in the GnomAD database, including 12,574 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 0.098 (865 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11709 hom.)
• Consequence: TNFRSF11B NM_002546.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002784
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.139
• Publications: 13 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-118926486-T-G is Benign according to our data. Variant chr8-118926486-T-G is described in ClinVar as Benign. ClinVar VariationId is 258774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.817+8A>C		splice_region_variant, intron_variant	Intron 4 of 4	ENST00000297350.9	NP_002537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11B	ENST00000297350.9	c.817+8A>C		splice_region_variant, intron_variant	Intron 4 of 4	1	NM_002546.4	ENSP00000297350.4
TNFRSF11B	ENST00000521597.1	n.561+8A>C		splice_region_variant, intron_variant	Intron 2 of 2	2
TNFRSF11B	ENST00000517352.1	n.*668A>C		downstream_gene_variant		1		ENSP00000427924.1

Frequencies

GnomAD3 genomes AF: 0.0984 AC: 14968 AN: 152142 Hom.: 865 Cov.: 33

Gnomad AFR AF: 0.0537

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0756

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.00500

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0915

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.108

GnomAD2 exomes AF: 0.105 AC: 26374 AN: 251162 AF XY: 0.110

Gnomad AFR exome AF: 0.0519

Gnomad AMR exome AF: 0.0494

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.00723

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.122 AC: 176948 AN: 1450678 Hom.: 11709 Cov.: 30 AF XY: 0.123 AC XY: 88704 AN XY: 722520

African (AFR) AF: 0.0532 AC: 1770 AN: 33244

American (AMR) AF: 0.0520 AC: 2326 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3673 AN: 26048

East Asian (EAS) AF: 0.00399 AC: 158 AN: 39640

South Asian (SAS) AF: 0.137 AC: 11776 AN: 86002

European-Finnish (FIN) AF: 0.101 AC: 5369 AN: 53116

Middle Eastern (MID) AF: 0.112 AC: 643 AN: 5742

European-Non Finnish (NFE) AF: 0.131 AC: 144012 AN: 1102146

Other (OTH) AF: 0.120 AC: 7221 AN: 60036

GnomAD4 genome AF: 0.0984 AC: 14977 AN: 152260 Hom.: 865 Cov.: 33 AF XY: 0.0963 AC XY: 7172 AN XY: 74446

African (AFR) AF: 0.0537 AC: 2231 AN: 41556

American (AMR) AF: 0.0754 AC: 1153 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 468 AN: 3472

East Asian (EAS) AF: 0.00501 AC: 26 AN: 5190

South Asian (SAS) AF: 0.138 AC: 668 AN: 4830

European-Finnish (FIN) AF: 0.0915 AC: 970 AN: 10606

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

European-Non Finnish (NFE) AF: 0.134 AC: 9104 AN: 67994

Other (OTH) AF: 0.110 AC: 232 AN: 2112

Alfa AF: 0.115 Hom.: 735

Bravo AF: 0.0912

Asia WGS AF: 0.0950 AC: 331 AN: 3478

EpiCase AF: 0.129

EpiControl AF: 0.126

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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 13, 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	-0.83
CADD	Benign	0.58
DANN	Benign	0.48
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
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: rs7844539; hg19: chr8-119938725;