rs8094884

Variant names:

• chr18-62360895-G-A
• rs8094884
• NM_003839.4:c.617-785G>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.617-785G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 152,000 control chromosomes in the GnomAD database, including 13,358 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 0.41 (13358 hom., cov: 31)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.47
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.617-785G>A		intron_variant	Intron 6 of 9	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.617-785G>A		intron_variant	Intron 6 of 9	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11	c.616+846G>A		intron_variant	Intron 6 of 6	1		ENSP00000269485.7

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62253 AN: 151882 Hom.: 13358 Cov.: 31

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.449

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

GnomAD4 genome AF: 0.410 AC: 62270 AN: 152000 Hom.: 13358 Cov.: 31 AF XY: 0.402 AC XY: 29875 AN XY: 74278

African (AFR) AF: 0.375 AC: 15541 AN: 41422

American (AMR) AF: 0.429 AC: 6556 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1770 AN: 3466

East Asian (EAS) AF: 0.108 AC: 560 AN: 5180

South Asian (SAS) AF: 0.279 AC: 1341 AN: 4814

European-Finnish (FIN) AF: 0.369 AC: 3891 AN: 10558

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.457 AC: 31072 AN: 67968

Other (OTH) AF: 0.446 AC: 944 AN: 2116

Alfa AF: 0.453 Hom.: 27329

Bravo AF: 0.419

Asia WGS AF: 0.221 AC: 775 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.5
DANN	Benign	0.79
PhyloP100		2.5
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: rs8094884; hg19: chr18-60028128;