rs8092336

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003839.4(TNFRSF11A):c.933A>G(p.Thr311Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.944 in 1,614,226 control chromosomes in the GnomAD database, including 719,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.96 ( 70187 hom., cov: 32)

Exomes 𝑓: 0.94 ( 649501 hom. )

Consequence

TNFRSF11A
NM_003839.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.79

Publications

36 publications found

Variant links:

Genes affected

TNFRSF11A (HGNC:11908): (TNF receptor superfamily member 11a) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptors can interact with various TRAF family proteins, through which this receptor induces the activation of NF-kappa B and MAPK8/JNK. This receptor and its ligand are important regulators of the interaction between T cells and dendritic cells. This receptor is also an essential mediator for osteoclast and lymph node development. Mutations at this locus have been associated with familial expansile osteolysis, autosomal recessive osteopetrosis, and Paget disease of bone. Alternatively spliced transcript variants have been described for this locus. [provided by RefSeq, Aug 2012]

TNFRSF11A Gene-Disease associations (from GenCC):

Paget disease of bone 2, early-onset
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal recessive osteopetrosis 7
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet
familial expansile osteolysis
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
dysosteosclerosis
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
osteosarcoma
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

TNFRSF11A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 18-62368850-A-G is Benign according to our data. Variant chr18-62368850-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.79 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4 link	c.933A>G	p.Thr311Thr	synonymous_variant	Exon 9 of 10	ENST00000586569.3	NP_003830.1	Q9Y6Q6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3 link	c.933A>G	p.Thr311Thr	synonymous_variant	Exon 9 of 10	1	NM_003839.4	ENSP00000465500.1		Q9Y6Q6-1
TNFRSF11A	ENST00000269485.11 link	c.616+8801A>G		intron_variant	Intron 6 of 6	1		ENSP00000269485.7		Q9Y6Q6-2

Frequencies

GnomAD3 genomes

AF:

0.960

AC:

146061

AN:

152222

Hom.:

70123

Cov.:

show subpopulations

Gnomad AFR

AF:

0.989

Gnomad AMI

AF:

0.940

Gnomad AMR

AF:

0.974

Gnomad ASJ

AF:

0.960

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.961

Gnomad FIN

AF:

0.960

Gnomad MID

AF:

0.959

Gnomad NFE

AF:

0.935

Gnomad OTH

AF:

0.965

GnomAD2 exomes

AF:

0.958

AC:

240889

AN:

251488

AF XY:

0.956

show subpopulations

Gnomad AFR exome

AF:

0.991

Gnomad AMR exome

AF:

0.984

Gnomad ASJ exome

AF:

0.961

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.962

Gnomad NFE exome

AF:

0.937

Gnomad OTH exome

AF:

0.957

GnomAD4 exome

AF:

0.942

AC:

1377626

AN:

1461886

Hom.:

649501

Cov.:

AF XY:

0.942

AC XY:

685410

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.992

AC:

33210

AN:

33480

American (AMR)

AF:

0.983

AC:

43983

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.961

AC:

25111

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39696

AN:

39700

South Asian (SAS)

AF:

0.958

AC:

82648

AN:

86258

European-Finnish (FIN)

AF:

0.961

AC:

51311

AN:

53414

Middle Eastern (MID)

AF:

0.960

AC:

5540

AN:

5768

European-Non Finnish (NFE)

AF:

0.934

AC:

1038855

AN:

1112012

Other (OTH)

AF:

0.948

AC:

57272

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

5745

11490

17235

22980

28725

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21576

43152

64728

86304

107880

<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:

0.960

AC:

146183

AN:

152340

Hom.:

70187

Cov.:

AF XY:

0.962

AC XY:

71627

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.989

AC:

41113

AN:

41574

American (AMR)

AF:

0.974

AC:

14905

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.960

AC:

3334

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5181

AN:

5182

South Asian (SAS)

AF:

0.961

AC:

4642

AN:

4830

European-Finnish (FIN)

AF:

0.960

AC:

10194

AN:

10622

Middle Eastern (MID)

AF:

0.956

AC:

281

AN:

294

European-Non Finnish (NFE)

AF:

0.935

AC:

63634

AN:

68036

Other (OTH)

AF:

0.966

AC:

2042

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

302

605

907

1210

1512

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.946

Hom.:

134802

Bravo

AF:

0.964

Asia WGS

AF:

0.986

AC:

3429

AN:

3478

EpiCase

AF:

0.941

EpiControl

AF:

0.940

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial expansile osteolysis

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bone Paget disease

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteopetrosis

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive osteopetrosis 7

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.21

(source)

DANN

Benign

0.30

PhyloP100

-1.8

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over