Genetic Variant TNFRSF11B:c.*367G>A (chr8-118924007-C-T) – 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.*367G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0693 in 182,516 control chromosomes in the GnomAD database, including 1,737 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 1717 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 20 hom. )

Consequence

TNFRSF11B
NM_002546.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.06

Publications

1 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=-0.48).

BP6

Variant 8-118924007-C-T is Benign according to our data. Variant chr8-118924007-C-T is described in ClinVar as Benign. ClinVar VariationId is 361685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.279 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.*367G>A		3_prime_UTR	Exon 5 of 5	NP_002537.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TNFRSF11B	ENST00000297350.9	TSL:1 MANE Select	c.*367G>A	3_prime_UTR	Exon 5 of 5	ENSP00000297350.4	O00300
TNFRSF11B	ENST00000966248.1		c.*367G>A	3_prime_UTR	Exon 5 of 5	ENSP00000636307.1
TNFRSF11B	ENST00000903853.1		c.*367G>A	3_prime_UTR	Exon 4 of 4	ENSP00000573912.1

Frequencies

GnomAD3 genomes

AF:

0.0819

AC:

12426

AN:

151696

Hom.:

1711

Cov.:

show subpopulations

Gnomad AFR

AF:

0.283

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.0627

GnomAD4 exome

AF:

0.00612

AC:

188

AN:

30718

Hom.:

Cov.:

AF XY:

0.00594

AC XY:

AN XY:

16156

show subpopulations

African (AFR)

AF:

0.181

AC:

102

AN:

562

American (AMR)

AF:

0.0183

AC:

AN:

3120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

748

East Asian (EAS)

AF:

0.00

AC:

AN:

2216

South Asian (SAS)

AF:

0.000551

AC:

AN:

3632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1462

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000346

AC:

AN:

17348

Other (OTH)

AF:

0.0129

AC:

AN:

1550

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0820

AC:

12454

AN:

151798

Hom.:

1717

Cov.:

AF XY:

0.0785

AC XY:

5822

AN XY:

74178

show subpopulations

African (AFR)

AF:

0.283

AC:

11721

AN:

41392

American (AMR)

AF:

0.0328

AC:

501

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00104

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10422

Middle Eastern (MID)

AF:

0.0276

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00129

AC:

AN:

67958

Other (OTH)

AF:

0.0622

AC:

131

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

480

959

1439

1918

2398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0283

Hom.:

1309

Bravo

AF:

0.0935

Asia WGS

AF:

0.0130

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperphosphatasemia with bone disease (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

1.1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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