rs138818878

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003701.4(TNFSF11):c.107C>G(p.Pro36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0274 in 1,570,004 control chromosomes in the GnomAD database, including 744 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 54 hom., cov: 34)

Exomes 𝑓: 0.028 ( 690 hom. )

Consequence

TNFSF11
NM_003701.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.50

Publications

8 publications found

Variant links:

Genes affected

TNFSF11 (HGNC:11926): (TNF superfamily member 11) This gene encodes a member of the tumor necrosis factor (TNF) cytokine family which is a ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation. This protein was shown to be a dentritic cell survival factor and is involved in the regulation of T cell-dependent immune response. T cell activation was reported to induce expression of this gene and lead to an increase of osteoclastogenesis and bone loss. This protein was shown to activate antiapoptotic kinase AKT/PKB through a signaling complex involving SRC kinase and tumor necrosis factor receptor-associated factor (TRAF) 6, which indicated this protein may have a role in the regulation of cell apoptosis. Targeted disruption of the related gene in mice led to severe osteopetrosis and a lack of osteoclasts. The deficient mice exhibited defects in early differentiation of T and B lymphocytes, and failed to form lobulo-alveolar mammary structures during pregnancy. Two alternatively spliced transcript variants have been found. [provided by RefSeq, Jul 2008]

TNFSF11 Gene-Disease associations (from GenCC):

autosomal recessive osteopetrosis 2
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
autosomal recessive osteopetrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TNFSF11 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=0.0021615326).

BP6

Variant 13-42574410-C-G is Benign according to our data. Variant chr13-42574410-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 312229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.021 (3191/152264) while in subpopulation NFE AF = 0.0318 (2161/68014). AF 95% confidence interval is 0.0307. There are 54 homozygotes in GnomAd4. There are 1559 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 54 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TNFSF11	NM_003701.4 link	c.107C>G	p.Pro36Arg	missense_variant	Exon 1 of 5	ENST00000398795.7	NP_003692.1
TNFSF11	NM_033012.4 link	c.-1+2672C>G		intron_variant	Intron 3 of 6		NP_143026.1
TNFSF11	XM_047430707.1 link	c.-1+2672C>G		intron_variant	Intron 1 of 4		XP_047286663.1
TNFSF11	XM_011535280.3 link	c.-595C>G		upstream_gene_variant			XP_011533582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF11	ENST00000398795.7 link	c.107C>G	p.Pro36Arg	missense_variant	Exon 1 of 5	1	NM_003701.4	ENSP00000381775.3
TNFSF11	ENST00000358545.6 link	c.-1+2672C>G		intron_variant	Intron 3 of 6	1		ENSP00000351347.2

Frequencies

GnomAD3 genomes

AF:

0.0210

AC:

3193

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00500

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.00750

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.0460

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0318

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.0197

AC:

3482

AN:

177200

AF XY:

0.0195

show subpopulations

Gnomad AFR exome

AF:

0.00513

Gnomad AMR exome

AF:

0.00854

Gnomad ASJ exome

AF:

0.00993

Gnomad EAS exome

AF:

0.0000725

Gnomad FIN exome

AF:

0.0439

Gnomad NFE exome

AF:

0.0287

Gnomad OTH exome

AF:

0.0186

GnomAD4 exome

AF:

0.0281

AC:

39808

AN:

1417740

Hom.:

690

Cov.:

AF XY:

0.0276

AC XY:

19342

AN XY:

701592

show subpopulations

African (AFR)

AF:

0.00494

AC:

161

AN:

32618

American (AMR)

AF:

0.00882

AC:

348

AN:

39440

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

234

AN:

25370

East Asian (EAS)

AF:

0.0000264

AC:

AN:

37906

South Asian (SAS)

AF:

0.0122

AC:

997

AN:

81400

European-Finnish (FIN)

AF:

0.0429

AC:

1983

AN:

46192

Middle Eastern (MID)

AF:

0.00557

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.0318

AC:

34691

AN:

1092044

Other (OTH)

AF:

0.0234

AC:

1370

AN:

58640

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

2434

4867

7301

9734

12168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1294

2588

3882

5176

6470

<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:

0.0210

AC:

3191

AN:

152264

Hom.:

Cov.:

AF XY:

0.0209

AC XY:

1559

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00496

AC:

206

AN:

41552

American (AMR)

AF:

0.0118

AC:

181

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00750

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.0118

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0460

AC:

488

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0318

AC:

2161

AN:

68014

Other (OTH)

AF:

0.0152

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

171

343

514

686

857

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0264

Hom.:

Bravo

AF:

0.0169

TwinsUK

AF:

0.0278

AC:

103

ALSPAC

AF:

0.0311

AC:

120

ESP6500AA

AF:

0.00618

AC:

ESP6500EA

AF:

0.0245

AC:

178

ExAC

AF:

0.0144

AC:

1641

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Increased bone mineral density

Benign:1

Mar 19, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive osteopetrosis 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

-0.045

Eigen_PC

Benign

-0.092

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0022

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.0

PhyloP100

1.5

PrimateAI

Uncertain

0.76

Sift4G

Uncertain

0.018

Vest4

0.083

ClinPred

0.013

GERP RS

3.8

PromoterAI

-0.075

Neutral

(source)

Varity_R

0.049

gMVP

0.27

Mutation Taster

=292/8

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over