rs3134046

Variant names:

• chr8-118928934-A-G
• rs3134046
• NM_002546.4:c.401-5T>C

Your query was ambiguous. Multiple possible variants found:

• chr8-118928934-A-G
• chr8-118928934-A-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.401-5T>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 0.942 in 1,613,910 control chromosomes in the GnomAD database, including 716,535 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 0.93 (66046 hom., cov: 32)
  • Exomes 𝑓: 0.94 (650489 hom.)
• Consequence: TNFRSF11B NM_002546.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009555
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.12
• Publications: 18 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=-0.81).
• BP6: Variant 8-118928934-A-G is Benign according to our data. Variant chr8-118928934-A-G is described in ClinVar as Benign. ClinVar VariationId is 196349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.401-5T>C		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.401-5T>C		splice_region_variant, intron_variant	Intron 2 of 4	1	NM_002546.4	ENSP00000297350.4
TNFRSF11B	ENST00000517352.1	n.*244-5T>C		splice_region_variant, intron_variant	Intron 3 of 4	1		ENSP00000427924.1
TNFRSF11B	ENST00000521597.1	n.140T>C		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes AF: 0.931 AC: 141654 AN: 152140 Hom.: 65990 Cov.: 32

Gnomad AFR AF: 0.920

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.938

Gnomad EAS AF: 0.869

Gnomad SAS AF: 0.967

Gnomad FIN AF: 0.961

Gnomad MID AF: 0.915

Gnomad NFE AF: 0.943

Gnomad OTH AF: 0.948

GnomAD2 exomes AF: 0.931 AC: 233981 AN: 251306 AF XY: 0.936

Gnomad AFR exome AF: 0.919

Gnomad AMR exome AF: 0.862

Gnomad ASJ exome AF: 0.938

Gnomad EAS exome AF: 0.867

Gnomad FIN exome AF: 0.965

Gnomad NFE exome AF: 0.947

Gnomad OTH exome AF: 0.938

GnomAD4 exome AF: 0.943 AC: 1378597 AN: 1461652 Hom.: 650489 Cov.: 45 AF XY: 0.944 AC XY: 686474 AN XY: 727158

African (AFR) AF: 0.918 AC: 30745 AN: 33474

American (AMR) AF: 0.869 AC: 38859 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.939 AC: 24544 AN: 26134

East Asian (EAS) AF: 0.873 AC: 34629 AN: 39688

South Asian (SAS) AF: 0.967 AC: 83369 AN: 86252

European-Finnish (FIN) AF: 0.962 AC: 51346 AN: 53386

Middle Eastern (MID) AF: 0.942 AC: 5435 AN: 5768

European-Non Finnish (NFE) AF: 0.947 AC: 1052854 AN: 1111862

Other (OTH) AF: 0.941 AC: 56816 AN: 60378

GnomAD4 genome AF: 0.931 AC: 141767 AN: 152258 Hom.: 66046 Cov.: 32 AF XY: 0.931 AC XY: 69298 AN XY: 74434

African (AFR) AF: 0.921 AC: 38238 AN: 41538

American (AMR) AF: 0.887 AC: 13565 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.938 AC: 3258 AN: 3472

East Asian (EAS) AF: 0.869 AC: 4484 AN: 5160

South Asian (SAS) AF: 0.967 AC: 4665 AN: 4824

European-Finnish (FIN) AF: 0.961 AC: 10203 AN: 10618

Middle Eastern (MID) AF: 0.915 AC: 269 AN: 294

European-Non Finnish (NFE) AF: 0.943 AC: 64168 AN: 68026

Other (OTH) AF: 0.949 AC: 2008 AN: 2116

Alfa AF: 0.935 Hom.: 34917

Bravo AF: 0.925

Asia WGS AF: 0.934 AC: 3250 AN: 3478

EpiCase AF: 0.947

EpiControl AF: 0.948

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

GeneDx

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:2

Mar 07, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperphosphatasemia with bone disease Benign:2

Jan 12, 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. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.9
DANN	Benign	0.56
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000096
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		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: rs3134046; hg19: chr8-119941173;