NM_003839.4:c.17G>A

Variant names:

• chr18-62325369-G-A
• rs1405874976
• NM_003839.4:c.17G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. 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. 13/22 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
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive osteopetrosis 7

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Orphanet, Genomics England PanelApp
• familial expansile osteolysis

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• dysosteosclerosis

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
• osteosarcoma

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003839.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	NM_003839.4	MANE Select	c.17G>A	p.Arg6Gln	missense	Exon 1 of 10	NP_003830.1	Q9Y6Q6-1
	TNFRSF11A	NM_001278268.2		c.17G>A	p.Arg6Gln	missense	Exon 1 of 10	NP_001265197.1	Q9Y6Q6-6
	TNFRSF11A	NM_001270950.2		c.17G>A	p.Arg6Gln	missense	Exon 1 of 8	NP_001257879.1	Q9Y6Q6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	ENST00000586569.3	TSL:1 MANE Select	c.17G>A	p.Arg6Gln	missense	Exon 1 of 10	ENSP00000465500.1	Q9Y6Q6-1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.17G>A	p.Arg6Gln	missense	Exon 1 of 7	ENSP00000269485.7	Q9Y6Q6-2
	TNFRSF11A	ENST00000903844.1		c.17G>A	p.Arg6Gln	missense	Exon 1 of 10	ENSP00000573903.1

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

African (AFR) AF: 0.00 AC: 0 AN: 17010

American (AMR) AF: 0.00 AC: 0 AN: 3514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7018

East Asian (EAS) AF: 0.00 AC: 0 AN: 7166

South Asian (SAS) AF: 0.00 AC: 0 AN: 19330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1914

European-Non Finnish (NFE) AF: 0.00000496 AC: 4 AN: 806646

Other (OTH) AF: 0.0000324 AC: 1 AN: 30834

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.55	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.093
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.046	D
Polyphen		0.0	B
Vest4		0.19
MutPred		0.22		Loss of methylation at R4 (P = 0.0337)
MVP		0.35
MPC		0.063
ClinPred		0.43	T
GERP RS		0.63
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.052
gMVP		0.38
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1405874976; hg19: chr18-59992602;