chr18-62325369-G-A

Position:

• chr18-62325369-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_003839.4(TNFRSF11A):​c.17G>A​(p.Arg6Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000556 in 898,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: TNFRSF11A NM_003839.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18281662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF11A	NM_003839.4	c.17G>A	p.Arg6Gln	missense_variant	1/10	ENST00000586569.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.17G>A	p.Arg6Gln	missense_variant	1/10	1	NM_003839.4	P2
TNFRSF11A	ENST00000269485.11	c.17G>A	p.Arg6Gln	missense_variant	1/7	1		A2
TNFRSF11A	ENST00000592013.1	n.44G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000556 AC: 5 AN: 898598 Hom.: 0 Cov.: 30 AF XY: 0.00000942 AC XY: 4 AN XY: 424430

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000496

Gnomad4 OTH exome AF: 0.0000324

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 13, 2022

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TNFRSF11A-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 6 of the TNFRSF11A protein (p.Arg6Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.55	T;T;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.76	T
Polyphen		0.0	.;.;.;.;B
Vest4		0.19, 0.17, 0.18, 0.20
MutPred		0.22		Loss of methylation at R4 (P = 0.0337);Loss of methylation at R4 (P = 0.0337);Loss of methylation at R4 (P = 0.0337);Loss of methylation at R4 (P = 0.0337);Loss of methylation at R4 (P = 0.0337);
MVP		0.35
MPC		0.063
ClinPred		0.43	T
GERP RS		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.052
gMVP		0.38

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

Other links and lift over

dbSNP: rs1405874976; hg19: chr18-59992602;