rs8089829

Variant names:

• chr18-62364671-A-G
• rs8089829
• NM_003839.4:c.731-2037A>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.731-2037A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 151,982 control chromosomes in the GnomAD database, including 15,655 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 0.45 (15655 hom., cov: 31)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.197
• Publications: 12 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.485 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.731-2037A>G		intron	N/A	NP_003830.1	Q9Y6Q6-1
	TNFRSF11A	NM_001278268.2		c.689-2037A>G		intron	N/A	NP_001265197.1	Q9Y6Q6-6
	TNFRSF11A	NM_001270950.2		c.730+2878A>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.731-2037A>G		intron	N/A	ENSP00000465500.1	Q9Y6Q6-1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.616+4622A>G		intron	N/A	ENSP00000269485.7	Q9Y6Q6-2
	TNFRSF11A	ENST00000903844.1		c.746-2037A>G		intron	N/A	ENSP00000573903.1

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68303 AN: 151864 Hom.: 15648 Cov.: 31

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.474

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

GnomAD4 genome AF: 0.450 AC: 68343 AN: 151982 Hom.: 15655 Cov.: 31 AF XY: 0.444 AC XY: 32970 AN XY: 74322

African (AFR) AF: 0.491 AC: 20337 AN: 41416

American (AMR) AF: 0.426 AC: 6500 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1768 AN: 3472

East Asian (EAS) AF: 0.281 AC: 1451 AN: 5170

South Asian (SAS) AF: 0.346 AC: 1670 AN: 4824

European-Finnish (FIN) AF: 0.391 AC: 4135 AN: 10564

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.454 AC: 30877 AN: 67948

Other (OTH) AF: 0.470 AC: 994 AN: 2114

Alfa AF: 0.444 Hom.: 7790

Bravo AF: 0.455

Asia WGS AF: 0.354 AC: 1232 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.7
DANN	Benign	0.75
PhyloP100		-0.20
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: rs8089829; hg19: chr18-60031904;