rs1564858

Variant names:

• chr8-118932927-G-A
• rs1564858
• NM_002546.4:c.400+4C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-118932927-G-A
• chr8-118932927-G-T

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.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
• Publications: 14 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=-0.94).
• BP6: Variant 8-118932927-G-A is Benign according to our data. Variant chr8-118932927-G-A is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.400+4C>T		splice_region_variant, intron_variant	Intron 2 of 4	ENST00000297350.9	NP_002537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11B	ENST00000297350.9	c.400+4C>T		splice_region_variant, intron_variant	Intron 2 of 4	1	NM_002546.4	ENSP00000297350.4
TNFRSF11B	ENST00000517352.1	n.400+4C>T		splice_region_variant, intron_variant	Intron 2 of 4	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

GnomAD2 exomes AF: 0.105 AC: 26347 AN: 250686 AF XY: 0.110

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 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

African (AFR) AF: 0.0558 AC: 1868 AN: 33480

American (AMR) AF: 0.0523 AC: 2338 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3807 AN: 26132

East Asian (EAS) AF: 0.00403 AC: 160 AN: 39700

South Asian (SAS) AF: 0.140 AC: 12055 AN: 86244

European-Finnish (FIN) AF: 0.102 AC: 5414 AN: 53316

Middle Eastern (MID) AF: 0.113 AC: 653 AN: 5768

European-Non Finnish (NFE) AF: 0.130 AC: 144761 AN: 1111926

Other (OTH) AF: 0.121 AC: 7337 AN: 60390

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

African (AFR) AF: 0.0561 AC: 2330 AN: 41534

American (AMR) AF: 0.0760 AC: 1162 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 479 AN: 3468

East Asian (EAS) AF: 0.00483 AC: 25 AN: 5174

South Asian (SAS) AF: 0.139 AC: 672 AN: 4820

European-Finnish (FIN) AF: 0.0918 AC: 972 AN: 10588

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9020 AN: 68006

Other (OTH) AF: 0.109 AC: 230 AN: 2114

Alfa AF: 0.119 Hom.: 2262

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

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	-0.94
CADD	Benign	0.035
DANN	Benign	0.52
PhyloP100		-1.8
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1564858; hg19: chr8-119945166;