18-62325389-G-A

Position:

chr18-62325389-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBS1_Supporting

The NM_003839.4(TNFRSF11A):c.37G>A(p.Ala13Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000455 in 1,121,108 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A13A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 1 hom. )

Consequence

TNFRSF11A
NM_003839.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.100

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a signal_peptide (size 28) in uniprot entity TNR11_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003839.4

BP4

Computational evidence support a benign effect (MetaRNN=0.009615183).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000536 (8/149162) while in subpopulation SAS AF= 0.00145 (7/4828). AF 95% confidence interval is 0.00068. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF11A	NM_003839.4 linkuse as main transcript	c.37G>A	p.Ala13Thr	missense_variant	1/10	ENST00000586569.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF11A	ENST00000586569.3 linkuse as main transcript	c.37G>A	p.Ala13Thr	missense_variant	1/10	1	NM_003839.4	P2	Q9Y6Q6-1
TNFRSF11A	ENST00000269485.11 linkuse as main transcript	c.37G>A	p.Ala13Thr	missense_variant	1/7	1		A2	Q9Y6Q6-2
TNFRSF11A	ENST00000592013.1 linkuse as main transcript	n.64G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000537

AC:

AN:

149056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000447

AC:

AN:

20116

Hom.:

AF XY:

0.000560

AC XY:

AN XY:

12492

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00187

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000442

AC:

AN:

971946

Hom.:

Cov.:

AF XY:

0.0000474

AC XY:

AN XY:

463790

show subpopulations

Gnomad4 AFR exome

AF:

0.0000537

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00164

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000118

Gnomad4 OTH exome

AF:

0.0000286

GnomAD4 genome

AF:

0.0000536

AC:

AN:

149162

Hom.:

Cov.:

AF XY:

0.0000962

AC XY:

AN XY:

72774

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000880

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 13 of the TNFRSF11A protein (p.Ala13Thr). This variant is present in population databases (rs781379689, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with TNFRSF11A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1911305). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.46

T;T;T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.0096

T;T;T;T;T

MetaSVM

Benign

-0.87

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.76

Polyphen

0.98

.;.;.;.;D

Vest4

0.27, 0.28, 0.28, 0.24

MutPred

0.33

Loss of MoRF binding (P = 0.1368);Loss of MoRF binding (P = 0.1368);Loss of MoRF binding (P = 0.1368);Loss of MoRF binding (P = 0.1368);Loss of MoRF binding (P = 0.1368);

MVP

0.75

MPC

0.055

ClinPred

0.070

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.065

gMVP

0.33

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over