rs9948182

Variant names:

• chr18-62380256-G-A
• rs9948182
• NM_003839.4:c.1568-4495G>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.1568-4495G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 151,890 control chromosomes in the GnomAD database, including 7,290 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 0.31 (7290 hom., cov: 32)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.584
• Publications: 4 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.33 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.1568-4495G>A		intron	N/A	NP_003830.1	Q9Y6Q6-1
	TNFRSF11A	NM_001278268.2		c.1526-4495G>A		intron	N/A	NP_001265197.1	Q9Y6Q6-6
	TNFRSF11A	NM_001270950.2		c.731-4495G>A		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.1568-4495G>A		intron	N/A	ENSP00000465500.1	Q9Y6Q6-1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.617-4495G>A		intron	N/A	ENSP00000269485.7	Q9Y6Q6-2
	TNFRSF11A	ENST00000903844.1		c.1583-4495G>A		intron	N/A	ENSP00000573903.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46296 AN: 151772 Hom.: 7283 Cov.: 32

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.0914

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.305

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

GnomAD4 genome AF: 0.305 AC: 46341 AN: 151890 Hom.: 7290 Cov.: 32 AF XY: 0.300 AC XY: 22291 AN XY: 74234

African (AFR) AF: 0.298 AC: 12350 AN: 41376

American (AMR) AF: 0.281 AC: 4289 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1185 AN: 3472

East Asian (EAS) AF: 0.0916 AC: 474 AN: 5176

South Asian (SAS) AF: 0.158 AC: 763 AN: 4820

European-Finnish (FIN) AF: 0.342 AC: 3596 AN: 10522

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22641 AN: 67948

Other (OTH) AF: 0.307 AC: 647 AN: 2108

Alfa AF: 0.325 Hom.: 4157

Bravo AF: 0.304

Asia WGS AF: 0.177 AC: 619 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.9
DANN	Benign	0.82
PhyloP100		-0.58
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: rs9948182; hg19: chr18-60047489;