Genetic Variant TNFRSF11A:c.76-10355A>C (chr18-62337813-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003839.4(TNFRSF11A):c.76-10355A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 152,018 control chromosomes in the GnomAD database, including 29,263 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.62 ( 29263 hom., cov: 33)

Consequence

TNFRSF11A
NM_003839.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.13

Publications

9 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4 link	c.76-10355A>C		intron_variant	Intron 1 of 9	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.76-10355A>C		intron_variant	Intron 1 of 9	1	NM_003839.4	ENSP00000465500.1		Q9Y6Q6-1
TNFRSF11A	ENST00000269485.11 link	c.76-10355A>C		intron_variant	Intron 1 of 6	1		ENSP00000269485.7		Q9Y6Q6-2

Frequencies

GnomAD3 genomes

AF:

0.618

AC:

93907

AN:

151900

Hom.:

29218

Cov.:

show subpopulations

Gnomad AFR

AF:

0.676

Gnomad AMI

AF:

0.690

Gnomad AMR

AF:

0.628

Gnomad ASJ

AF:

0.548

Gnomad EAS

AF:

0.759

Gnomad SAS

AF:

0.651

Gnomad FIN

AF:

0.638

Gnomad MID

AF:

0.491

Gnomad NFE

AF:

0.568

Gnomad OTH

AF:

0.618

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.618

AC:

94005

AN:

152018

Hom.:

29263

Cov.:

AF XY:

0.623

AC XY:

46254

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.677

AC:

28031

AN:

41434

American (AMR)

AF:

0.628

AC:

9601

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.548

AC:

1901

AN:

3468

East Asian (EAS)

AF:

0.758

AC:

3918

AN:

5166

South Asian (SAS)

AF:

0.652

AC:

3137

AN:

4814

European-Finnish (FIN)

AF:

0.638

AC:

6743

AN:

10562

Middle Eastern (MID)

AF:

0.486

AC:

143

AN:

294

European-Non Finnish (NFE)

AF:

0.568

AC:

38601

AN:

67976

Other (OTH)

AF:

0.616

AC:

1301

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1854

3708

5561

7415

9269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

772

1544

2316

3088

3860

<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:

0.590

Hom.:

43805

Bravo

AF:

0.620

Asia WGS

AF:

0.706

AC:

2449

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.068

(source)

DANN

Benign

0.41

PhyloP100

-2.1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over