NM_002546.4:c.9C>G

Variant names:

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.9C>G(p.Asn3Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 1,590,136 control chromosomes in the GnomAD database, including 203,467 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 29575 hom., cov: 33)

Exomes 𝑓: 0.48 ( 173892 hom. )

Consequence

TNFRSF11B
NM_002546.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.933

Publications

265 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 (MetaRNN=6.884634E-7).

BP6

Variant 8-118951813-G-C is Benign according to our data. Variant chr8-118951813-G-C is described in ClinVar as Benign. ClinVar VariationId is 258775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.857 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.9C>G	p.Asn3Lys	missense	Exon 1 of 5	NP_002537.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFRSF11B	ENST00000297350.9	TSL:1 MANE Select	c.9C>G	p.Asn3Lys	missense	Exon 1 of 5	ENSP00000297350.4	O00300
TNFRSF11B	ENST00000517352.1	TSL:1	n.9C>G		non_coding_transcript_exon	Exon 1 of 5	ENSP00000427924.1	E5RFV7
TNFRSF11B	ENST00000966249.1		c.9C>G	p.Asn3Lys	missense	Exon 1 of 6	ENSP00000636308.1

Frequencies

GnomAD3 genomes

AF:

0.597

AC:

90803

AN:

152012

Hom.:

29521

Cov.:

show subpopulations

Gnomad AFR

AF:

0.864

Gnomad AMI

AF:

0.302

Gnomad AMR

AF:

0.549

Gnomad ASJ

AF:

0.547

Gnomad EAS

AF:

0.745

Gnomad SAS

AF:

0.578

Gnomad FIN

AF:

0.497

Gnomad MID

AF:

0.671

Gnomad NFE

AF:

0.459

Gnomad OTH

AF:

0.575

GnomAD2 exomes

AF:

0.522

AC:

108753

AN:

208262

AF XY:

0.518

show subpopulations

Gnomad AFR exome

AF:

0.873

Gnomad AMR exome

AF:

0.453

Gnomad ASJ exome

AF:

0.562

Gnomad EAS exome

AF:

0.747

Gnomad FIN exome

AF:

0.478

Gnomad NFE exome

AF:

0.452

Gnomad OTH exome

AF:

0.519

GnomAD4 exome

AF:

0.484

AC:

695774

AN:

1438006

Hom.:

173892

Cov.:

AF XY:

0.486

AC XY:

346119

AN XY:

712718

show subpopulations

African (AFR)

AF:

0.878

AC:

28872

AN:

32888

American (AMR)

AF:

0.458

AC:

19235

AN:

41962

Ashkenazi Jewish (ASJ)

AF:

0.559

AC:

14354

AN:

25684

East Asian (EAS)

AF:

0.727

AC:

27933

AN:

38406

South Asian (SAS)

AF:

0.568

AC:

46800

AN:

82426

European-Finnish (FIN)

AF:

0.480

AC:

24600

AN:

51298

Middle Eastern (MID)

AF:

0.632

AC:

3628

AN:

5742

European-Non Finnish (NFE)

AF:

0.454

AC:

498934

AN:

1100152

Other (OTH)

AF:

0.528

AC:

31418

AN:

59448

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

17633

35266

52899

70532

88165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15272

30544

45816

61088

76360

<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:

0.598

AC:

90910

AN:

152130

Hom.:

29575

Cov.:

AF XY:

0.600

AC XY:

44617

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.864

AC:

35897

AN:

41544

American (AMR)

AF:

0.549

AC:

8395

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.547

AC:

1899

AN:

3472

East Asian (EAS)

AF:

0.744

AC:

3817

AN:

5128

South Asian (SAS)

AF:

0.577

AC:

2788

AN:

4828

European-Finnish (FIN)

AF:

0.497

AC:

5262

AN:

10598

Middle Eastern (MID)

AF:

0.670

AC:

197

AN:

294

European-Non Finnish (NFE)

AF:

0.459

AC:

31164

AN:

67956

Other (OTH)

AF:

0.577

AC:

1216

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1671

3343

5014

6686

8357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

726

1452

2178

2904

3630

<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:

0.495

Hom.:

14781

Bravo

AF:

0.610

TwinsUK

AF:

0.447

AC:

1656

ALSPAC

AF:

0.454

AC:

1750

ESP6500AA

AF:

0.860

AC:

3767

ESP6500EA

AF:

0.450

AC:

3863

ExAC

AF:

0.497

AC:

58979

Asia WGS

AF:

0.682

AC:

2373

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 (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.18

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.0059

LIST_S2

Benign

0.23

MetaRNN

Benign

6.9e-7

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.9

PhyloP100

0.93

PrimateAI

Benign

0.30

PROVEAN

Benign

0.68

REVEL

Benign

0.15

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.015

MutPred

0.37

Gain of methylation at N3 (P = 0.0153)

MPC

0.31

ClinPred

0.012

GERP RS

5.3

PromoterAI

-0.0073

Neutral

(source)

Varity_R

0.066

gMVP

0.79

Mutation Taster

=85/15

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