rs12956925

Variant names:

• chr18-62346407-G-A
• rs12956925
• NM_003839.4:c.76-1761G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003839.4(TNFRSF11A):​c.76-1761G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,152 control chromosomes in the GnomAD database, including 2,055 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 0.16 (2055 hom., cov: 32)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.448
• Publications: 11 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.76-1761G>A		intron_variant	Intron 1 of 9	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.76-1761G>A		intron_variant	Intron 1 of 9	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11	c.76-1761G>A		intron_variant	Intron 1 of 6	1		ENSP00000269485.7

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24063 AN: 152034 Hom.: 2054 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.160

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.158 AC: 24081 AN: 152152 Hom.: 2055 Cov.: 32 AF XY: 0.161 AC XY: 11992 AN XY: 74380

African (AFR) AF: 0.114 AC: 4718 AN: 41498

American (AMR) AF: 0.197 AC: 3010 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 519 AN: 3470

East Asian (EAS) AF: 0.109 AC: 562 AN: 5172

South Asian (SAS) AF: 0.219 AC: 1056 AN: 4826

European-Finnish (FIN) AF: 0.212 AC: 2246 AN: 10582

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11463 AN: 67988

Other (OTH) AF: 0.160 AC: 338 AN: 2116

Alfa AF: 0.165 Hom.: 6301

Bravo AF: 0.153

Asia WGS AF: 0.189 AC: 654 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.77
DANN	Benign	0.36
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

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: rs12956925; hg19: chr18-60013640;