dbSNP rs17069895: TNFRSF11A:c.617-55C>T (chr18-62361625-C-T) – 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.617-55C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00694 in 1,514,404 control chromosomes in the GnomAD database, including 637 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 0.0091 ( 79 hom., cov: 32)

Exomes 𝑓: 0.0067 ( 558 hom. )

Consequence

TNFRSF11A
NM_003839.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.19

Publications

3 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4 link	c.617-55C>T		intron_variant	Intron 6 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.617-55C>T		intron_variant	Intron 6 of 9	1	NM_003839.4	ENSP00000465500.1		Q9Y6Q6-1
TNFRSF11A	ENST00000269485.11 link	c.616+1576C>T		intron_variant	Intron 6 of 6	1		ENSP00000269485.7		Q9Y6Q6-2

Frequencies

GnomAD3 genomes

AF:

0.00915

AC:

1393

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0182

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.168

Gnomad SAS

AF:

0.00890

Gnomad FIN

AF:

0.00443

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.00765

GnomAD4 exome

AF:

0.00670

AC:

9120

AN:

1362118

Hom.:

558

AF XY:

0.00635

AC XY:

4340

AN XY:

683586

show subpopulations

African (AFR)

AF:

0.000574

AC:

AN:

31356

American (AMR)

AF:

0.0339

AC:

1512

AN:

44562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25526

East Asian (EAS)

AF:

0.156

AC:

6109

AN:

39146

South Asian (SAS)

AF:

0.00439

AC:

369

AN:

84090

European-Finnish (FIN)

AF:

0.00329

AC:

175

AN:

53250

Middle Eastern (MID)

AF:

0.00125

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

0.000486

AC:

496

AN:

1021476

Other (OTH)

AF:

0.00760

AC:

434

AN:

57114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

472

944

1415

1887

2359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.00911

AC:

1388

AN:

152286

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

772

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

41560

American (AMR)

AF:

0.0183

AC:

279

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.167

AC:

868

AN:

5184

South Asian (SAS)

AF:

0.00870

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00443

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000941

AC:

AN:

68026

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00636

Hom.:

Bravo

AF:

0.0120

Asia WGS

AF:

0.0570

AC:

198

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.23

(source)

DANN

Benign

0.75

PhyloP100

-2.2

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

Computational scores

Splicing

Publications

Other links and lift over