rs2073618

Positions:

chr8-118951813-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000297350.9(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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N3H) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.48 ( 173892 hom. )

Consequence

TNFRSF11B
ENST00000297350.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.933

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 258775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-118951813-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4 linkuse as main transcript	c.9C>G	p.Asn3Lys	missense_variant	1/5	ENST00000297350.9	NP_002537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF11B	ENST00000297350.9 linkuse as main transcript	c.9C>G	p.Asn3Lys	missense_variant	1/5	1	NM_002546.4	ENSP00000297350	P1
TNFRSF11B	ENST00000517352.1 linkuse as main transcript	c.9C>G	p.Asn3Lys	missense_variant, NMD_transcript_variant	1/5	1		ENSP00000427924

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

GnomAD3 exomes

AF:

0.522

AC:

108753

AN:

208262

Hom.:

29941

AF XY:

0.518

AC XY:

58179

AN XY:

112388

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 SAS exome

AF:

0.567

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

Gnomad4 AFR exome

AF:

0.878

Gnomad4 AMR exome

AF:

0.458

Gnomad4 ASJ exome

AF:

0.559

Gnomad4 EAS exome

AF:

0.727

Gnomad4 SAS exome

AF:

0.568

Gnomad4 FIN exome

AF:

0.480

Gnomad4 NFE exome

AF:

0.454

Gnomad4 OTH exome

AF:

0.528

GnomAD4 genome

AF:

0.598

AC:

90910

AN:

152130

Hom.:

29575

Cov.:

AF XY:

0.600

AC XY:

44617

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.864

Gnomad4 AMR

AF:

0.549

Gnomad4 ASJ

AF:

0.547

Gnomad4 EAS

AF:

0.744

Gnomad4 SAS

AF:

0.577

Gnomad4 FIN

AF:

0.497

Gnomad4 NFE

AF:

0.459

Gnomad4 OTH

AF:

0.577

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

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 28728263, 25679449, 12096838, 18938269, 20205168, 15312251, 19131500, 19128145, 22965192, 19705167) -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 28, 2017	- -

Hyperphosphatasemia with bone disease

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

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

MutationTaster

Benign

1.0

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

Varity_R

0.066

gMVP

0.79

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over