rs12959396

Variant names:

• chr18-62372076-T-G
• rs12959396
• NM_003839.4:c.1567+2592T>G

Variant summary

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

The NM_003839.4(TNFRSF11A):​c.1567+2592T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 152,014 control chromosomes in the GnomAD database, including 13,140 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 0.40 (13140 hom., cov: 32)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• Publications: 17 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

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.1567+2592T>G		intron	N/A	NP_003830.1	Q9Y6Q6-1
	TNFRSF11A	NM_001278268.2		c.1525+2592T>G		intron	N/A	NP_001265197.1	Q9Y6Q6-6
	TNFRSF11A	NM_001270950.2		c.730+10283T>G		intron	N/A	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.1567+2592T>G		intron	N/A	ENSP00000465500.1	Q9Y6Q6-1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.616+12027T>G		intron	N/A	ENSP00000269485.7	Q9Y6Q6-2
	TNFRSF11A	ENST00000903844.1		c.1582+2592T>G		intron	N/A	ENSP00000573903.1

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61296 AN: 151896 Hom.: 13130 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.430

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

GnomAD4 genome AF: 0.404 AC: 61344 AN: 152014 Hom.: 13140 Cov.: 32 AF XY: 0.399 AC XY: 29641 AN XY: 74306

African (AFR) AF: 0.315 AC: 13041 AN: 41454

American (AMR) AF: 0.449 AC: 6863 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 1525 AN: 3466

East Asian (EAS) AF: 0.160 AC: 826 AN: 5172

South Asian (SAS) AF: 0.230 AC: 1107 AN: 4810

European-Finnish (FIN) AF: 0.447 AC: 4706 AN: 10536

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.467 AC: 31780 AN: 67990

Other (OTH) AF: 0.428 AC: 903 AN: 2110

Alfa AF: 0.450 Hom.: 36314

Bravo AF: 0.404

Asia WGS AF: 0.247 AC: 862 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.44
DANN	Benign	0.66
PhyloP100		-1.5
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: rs12959396; hg19: chr18-60039309;