18-62354434-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_003839.4(TNFRSF11A):c.327C>T(p.Pro109Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00747 in 1,597,710 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P109P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0050 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0077 ( 61 hom. )

Consequence

TNFRSF11A
NM_003839.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.110

Publications

2 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 18-62354434-C-T is Benign according to our data. Variant chr18-62354434-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.11 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00499 (760/152360) while in subpopulation NFE AF = 0.00839 (571/68032). AF 95% confidence interval is 0.00782. There are 4 homozygotes in GnomAd4. There are 321 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4 link	c.327C>T	p.Pro109Pro	synonymous_variant	Exon 4 of 10	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3 link	c.327C>T	p.Pro109Pro	synonymous_variant	Exon 4 of 10	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11 link	c.327C>T	p.Pro109Pro	synonymous_variant	Exon 4 of 7	1		ENSP00000269485.7

Frequencies

GnomAD3 genomes

AF:

0.00499

AC:

759

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00838

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00541

AC:

1199

AN:

221482

AF XY:

0.00558

show subpopulations

Gnomad AFR exome

AF:

0.000819

Gnomad AMR exome

AF:

0.00195

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00184

Gnomad NFE exome

AF:

0.00835

Gnomad OTH exome

AF:

0.00588

GnomAD4 exome

AF:

0.00773

AC:

11169

AN:

1445350

Hom.:

Cov.:

AF XY:

0.00770

AC XY:

5540

AN XY:

719110

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

33384

American (AMR)

AF:

0.00214

AC:

AN:

44462

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

269

AN:

26002

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39592

South Asian (SAS)

AF:

0.00474

AC:

407

AN:

85824

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

41286

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

5138

European-Non Finnish (NFE)

AF:

0.00885

AC:

9819

AN:

1109732

Other (OTH)

AF:

0.00676

AC:

405

AN:

59930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

696

1392

2087

2783

3479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

372

744

1116

1488

1860

<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:

0.00499

AC:

760

AN:

152360

Hom.:

Cov.:

AF XY:

0.00431

AC XY:

321

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41590

American (AMR)

AF:

0.00268

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3472

East Asian (EAS)

AF:

0.000580

AC:

AN:

5174

South Asian (SAS)

AF:

0.00455

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00839

AC:

571

AN:

68032

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

123

164

205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00633

Hom.:

Bravo

AF:

0.00473

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TNFRSF11A: BP4, BP7, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Feb 11, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely 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

-0.37

CADD

Benign

5.7

(source)

DANN

Benign

0.89

PhyloP100

0.11

Mutation Taster

=100/0

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over