18-62325368-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003839.4(TNFRSF11A):c.16C>G(p.Arg6Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000767 in 1,043,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Consequence

TNFRSF11A
NM_003839.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.287

Publications

0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal recessive osteopetrosis 7
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Orphanet, Genomics England PanelApp
familial expansile osteolysis
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
dysosteosclerosis
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21859553).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003839.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFRSF11A	NM_003839.4	MANE Select	c.16C>G	p.Arg6Gly	missense	Exon 1 of 10	NP_003830.1	Q9Y6Q6-1
TNFRSF11A	NM_001278268.2		c.16C>G	p.Arg6Gly	missense	Exon 1 of 10	NP_001265197.1	Q9Y6Q6-6
TNFRSF11A	NM_001270950.2		c.16C>G	p.Arg6Gly	missense	Exon 1 of 8	NP_001257879.1	Q9Y6Q6-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFRSF11A	ENST00000586569.3	TSL:1 MANE Select	c.16C>G	p.Arg6Gly	missense	Exon 1 of 10	ENSP00000465500.1	Q9Y6Q6-1
TNFRSF11A	ENST00000269485.11	TSL:1	c.16C>G	p.Arg6Gly	missense	Exon 1 of 7	ENSP00000269485.7	Q9Y6Q6-2
TNFRSF11A	ENST00000903844.1		c.16C>G	p.Arg6Gly	missense	Exon 1 of 10	ENSP00000573903.1

Frequencies

GnomAD3 genomes

AF:

0.0000475

AC:

AN:

147448

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000112

AC:

AN:

895604

Hom.:

Cov.:

AF XY:

0.00000236

AC XY:

AN XY:

422902

show subpopulations

African (AFR)

AF:

0.0000590

AC:

AN:

16954

American (AMR)

AF:

0.00

AC:

AN:

3398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6900

East Asian (EAS)

AF:

0.00

AC:

AN:

6866

South Asian (SAS)

AF:

0.00

AC:

AN:

19228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4844

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1906

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

804858

Other (OTH)

AF:

0.00

AC:

AN:

30650

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000475

AC:

AN:

147448

Hom.:

Cov.:

AF XY:

0.0000418

AC XY:

AN XY:

71790

show subpopulations

African (AFR)

AF:

0.000171

AC:

AN:

40930

American (AMR)

AF:

0.00

AC:

AN:

14846

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3408

East Asian (EAS)

AF:

0.00

AC:

AN:

5098

South Asian (SAS)

AF:

0.00

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8768

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66354

Other (OTH)

AF:

0.00

AC:

AN:

2038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000718

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.040

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.51

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.20

PhyloP100

0.29

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.61

REVEL

Benign

0.18

Sift

Uncertain

0.011

Sift4G

Uncertain

0.015

Polyphen

0.020

Vest4

0.21

MutPred

0.29

Gain of relative solvent accessibility (P = 0.0275)

MVP

0.45

MPC

0.069

ClinPred

0.25

GERP RS

1.7

PromoterAI

0.0078

Neutral

(source)

Varity_R

0.093

gMVP

0.52

Mutation Taster

=90/10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over