Genetic Variant TNFRSF11A:p.Ala13Pro (chr18-62325389-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003839.4(TNFRSF11A):c.37G>C(p.Ala13Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A13T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TNFRSF11A
NM_003839.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.100

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: 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2699633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4 link	c.37G>C	p.Ala13Pro	missense_variant	Exon 1 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.37G>C	p.Ala13Pro	missense_variant	Exon 1 of 10	1	NM_003839.4	ENSP00000465500.1	Q9Y6Q6-1
TNFRSF11A	ENST00000269485.11 link	c.37G>C	p.Ala13Pro	missense_variant	Exon 1 of 7	1		ENSP00000269485.7	Q9Y6Q6-2
TNFRSF11A	ENST00000592013.1 link	n.64G>C		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

971946

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

463790

African (AFR)

AF:

0.00

AC:

AN:

18616

American (AMR)

AF:

0.00

AC:

AN:

7012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10302

East Asian (EAS)

AF:

0.00

AC:

AN:

13172

South Asian (SAS)

AF:

0.00

AC:

AN:

24354

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2328

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

849868

Other (OTH)

AF:

0.00

AC:

AN:

35016

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.060

.;.;.;.;T

Eigen

Benign

-0.055

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.37

T;T;T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.27

T;T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.55

.;N;N;N;N

PhyloP100

0.10

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.1

.;N;.;.;.

REVEL

Uncertain

0.31

Sift

Benign

0.41

.;T;.;.;.

Sift4G

Benign

0.073

.;T;D;T;T

Polyphen

1.0

.;.;.;.;D

Vest4

0.37, 0.35, 0.37, 0.34

MutPred

0.51

Gain of glycosylation at A13 (P = 0.0156);Gain of glycosylation at A13 (P = 0.0156);Gain of glycosylation at A13 (P = 0.0156);Gain of glycosylation at A13 (P = 0.0156);Gain of glycosylation at A13 (P = 0.0156);

MVP

0.97

MPC

0.070

ClinPred

0.44

GERP RS

1.9

PromoterAI

-0.047

Neutral

(source)

Varity_R

0.37

gMVP

0.45

Mutation Taster

=93/7

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over