dbSNP rs3102734: TNFRSF11B:c.30+15C>T (chr8-118951777-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002546.4(TNFRSF11B):c.30+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0616 in 1,585,750 control chromosomes in the GnomAD database, including 3,784 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.094 ( 834 hom., cov: 33)

Exomes 𝑓: 0.058 ( 2950 hom. )

Consequence

TNFRSF11B
NM_002546.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.205

Publications

22 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

TNFRSF11B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 8-118951777-G-A is Benign according to our data. Variant chr8-118951777-G-A is described in ClinVar as Benign. ClinVar VariationId is 361696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002546.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11B	NM_002546.4	MANE Select	c.30+15C>T		intron	N/A	NP_002537.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TNFRSF11B	ENST00000297350.9	TSL:1 MANE Select	c.30+15C>T	intron	N/A	ENSP00000297350.4	O00300
TNFRSF11B	ENST00000517352.1	TSL:1	n.30+15C>T	intron	N/A	ENSP00000427924.1	E5RFV7
TNFRSF11B	ENST00000966249.1		c.30+15C>T	intron	N/A	ENSP00000636308.1

Frequencies

GnomAD3 genomes

AF:

0.0936

AC:

14236

AN:

152096

Hom.:

826

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.0614

Gnomad EAS

AF:

0.128

Gnomad SAS

AF:

0.0387

Gnomad FIN

AF:

0.0386

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0560

Gnomad OTH

AF:

0.0675

GnomAD2 exomes

AF:

0.0726

AC:

14531

AN:

200110

AF XY:

0.0668

show subpopulations

Gnomad AFR exome

AF:

0.167

Gnomad AMR exome

AF:

0.131

Gnomad ASJ exome

AF:

0.0616

Gnomad EAS exome

AF:

0.126

Gnomad FIN exome

AF:

0.0330

Gnomad NFE exome

AF:

0.0513

Gnomad OTH exome

AF:

0.0669

GnomAD4 exome

AF:

0.0582

AC:

83398

AN:

1433538

Hom.:

2950

Cov.:

AF XY:

0.0572

AC XY:

40650

AN XY:

710284

show subpopulations

African (AFR)

AF:

0.168

AC:

5511

AN:

32752

American (AMR)

AF:

0.126

AC:

5219

AN:

41274

Ashkenazi Jewish (ASJ)

AF:

0.0607

AC:

1555

AN:

25604

East Asian (EAS)

AF:

0.120

AC:

4545

AN:

38018

South Asian (SAS)

AF:

0.0361

AC:

2958

AN:

81968

European-Finnish (FIN)

AF:

0.0373

AC:

1900

AN:

50888

Middle Eastern (MID)

AF:

0.0579

AC:

332

AN:

5738

European-Non Finnish (NFE)

AF:

0.0524

AC:

57550

AN:

1097996

Other (OTH)

AF:

0.0646

AC:

3828

AN:

59300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

3581

7163

10744

14326

17907

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2278

4556

6834

9112

11390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0936

AC:

14252

AN:

152212

Hom.:

834

Cov.:

AF XY:

0.0925

AC XY:

6887

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.167

AC:

6945

AN:

41516

American (AMR)

AF:

0.122

AC:

1861

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0614

AC:

213

AN:

3470

East Asian (EAS)

AF:

0.128

AC:

658

AN:

5156

South Asian (SAS)

AF:

0.0384

AC:

185

AN:

4822

European-Finnish (FIN)

AF:

0.0386

AC:

410

AN:

10616

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0560

AC:

3809

AN:

68012

Other (OTH)

AF:

0.0663

AC:

140

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

661

1322

1982

2643

3304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0745

Hom.:

205

Bravo

AF:

0.103

Asia WGS

AF:

0.0730

AC:

256

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hyperphosphatasemia with bone disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

-0.20

PromoterAI

0.019

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over