NM_003839.4:c.575C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003839.4(TNFRSF11A):c.575C>T(p.Ala192Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,612,518 control chromosomes in the GnomAD database, including 221,917 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. A192A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.56 ( 24523 hom., cov: 32)

Exomes 𝑓: 0.52 ( 197394 hom. )

Consequence

TNFRSF11A
NM_003839.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.391

Publications

111 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.930566E-6).

BP6

Variant 18-62360008-C-T is Benign according to our data. Variant chr18-62360008-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4 link	c.575C>T	p.Ala192Val	missense_variant	Exon 6 of 10	ENST00000586569.3	NP_003830.1	Q9Y6Q6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNFRSF11A	ENST00000586569.3 link	c.575C>T	p.Ala192Val	missense_variant	Exon 6 of 10	1	NM_003839.4	ENSP00000465500.1	Q9Y6Q6-1
TNFRSF11A	ENST00000269485.11 link	c.575C>T	p.Ala192Val	missense_variant	Exon 6 of 7	1		ENSP00000269485.7	Q9Y6Q6-2
TNFRSF11A	ENST00000587697.1 link	n.493C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.563

AC:

85554

AN:

151866

Hom.:

24478

Cov.:

show subpopulations

Gnomad AFR

AF:

0.639

Gnomad AMI

AF:

0.491

Gnomad AMR

AF:

0.625

Gnomad ASJ

AF:

0.545

Gnomad EAS

AF:

0.690

Gnomad SAS

AF:

0.411

Gnomad FIN

AF:

0.529

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.511

Gnomad OTH

AF:

0.600

GnomAD2 exomes

AF:

0.545

AC:

136972

AN:

251466

AF XY:

0.531

show subpopulations

Gnomad AFR exome

AF:

0.646

Gnomad AMR exome

AF:

0.664

Gnomad ASJ exome

AF:

0.551

Gnomad EAS exome

AF:

0.699

Gnomad FIN exome

AF:

0.532

Gnomad NFE exome

AF:

0.510

Gnomad OTH exome

AF:

0.543

GnomAD4 exome

AF:

0.516

AC:

753844

AN:

1460534

Hom.:

197394

Cov.:

AF XY:

0.512

AC XY:

371717

AN XY:

726618

show subpopulations

African (AFR)

AF:

0.643

AC:

21515

AN:

33448

American (AMR)

AF:

0.664

AC:

29671

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.545

AC:

14224

AN:

26120

East Asian (EAS)

AF:

0.687

AC:

27281

AN:

39686

South Asian (SAS)

AF:

0.399

AC:

34427

AN:

86234

European-Finnish (FIN)

AF:

0.532

AC:

28380

AN:

53382

Middle Eastern (MID)

AF:

0.515

AC:

2968

AN:

5766

European-Non Finnish (NFE)

AF:

0.507

AC:

563500

AN:

1110838

Other (OTH)

AF:

0.528

AC:

31878

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

19064

38129

57193

76258

95322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.564

AC:

85661

AN:

151984

Hom.:

24523

Cov.:

AF XY:

0.565

AC XY:

41959

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.640

AC:

26524

AN:

41468

American (AMR)

AF:

0.626

AC:

9547

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.545

AC:

1892

AN:

3472

East Asian (EAS)

AF:

0.691

AC:

3577

AN:

5178

South Asian (SAS)

AF:

0.412

AC:

1983

AN:

4818

European-Finnish (FIN)

AF:

0.529

AC:

5576

AN:

10544

Middle Eastern (MID)

AF:

0.561

AC:

165

AN:

294

European-Non Finnish (NFE)

AF:

0.511

AC:

34701

AN:

67950

Other (OTH)

AF:

0.596

AC:

1249

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1904

3807

5711

7614

9518

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.529

Hom.:

107962

Bravo

AF:

0.580

TwinsUK

AF:

0.505

AC:

1872

ALSPAC

AF:

0.528

AC:

2035

ESP6500AA

AF:

0.632

AC:

2786

ESP6500EA

AF:

0.511

AC:

4397

ExAC

AF:

0.537

AC:

65161

Asia WGS

AF:

0.569

AC:

1979

AN:

3478

EpiCase

AF:

0.521

EpiControl

AF:

0.524

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20564239, 21987421) -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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: Frequency -

Increased bone mineral density

Benign:1

Jun 17, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.14

.;.;.;.;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.26

T;T;T;T;T

MetaRNN

Benign

0.0000059

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.81

.;N;N;N;N

PhyloP100

0.39

PrimateAI

Benign

0.37

PROVEAN

Benign

1.4

.;N;.;.;.

REVEL

Benign

0.047

Sift

Benign

1.0

.;T;.;.;.

Sift4G

Benign

1.0

.;T;T;T;T

Polyphen

0.012

.;.;.;.;B

Vest4

0.083, 0.067, 0.049

MPC

1.1

ClinPred

0.0027

GERP RS

2.6

Varity_R

0.024

gMVP

0.75

Mutation Taster

=98/2

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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NM_003839.4:c.575C>T

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