NM_003839.4:c.428-1687G>A

Variant names:

• chr18-62356561-G-A
• rs9951012
• NM_003839.4:c.428-1687G>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.428-1687G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 152,058 control chromosomes in the GnomAD database, including 4,300 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 0.23 (4300 hom., cov: 33)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.904
• Publications: 5 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.309 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	NM_003839.4	MANE Select	c.428-1687G>A		intron	N/A	NP_003830.1
	TNFRSF11A	NM_001278268.2		c.428-1729G>A		intron	N/A	NP_001265197.1
	TNFRSF11A	NM_001270950.2		c.428-1687G>A		intron	N/A	NP_001257879.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	ENST00000586569.3	TSL:1 MANE Select	c.428-1687G>A		intron	N/A	ENSP00000465500.1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.428-1687G>A		intron	N/A	ENSP00000269485.7

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35301 AN: 151938 Hom.: 4292 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.232

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

GnomAD4 genome AF: 0.232 AC: 35330 AN: 152058 Hom.: 4300 Cov.: 33 AF XY: 0.238 AC XY: 17689 AN XY: 74332

African (AFR) AF: 0.219 AC: 9074 AN: 41462

American (AMR) AF: 0.299 AC: 4574 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 668 AN: 3468

East Asian (EAS) AF: 0.321 AC: 1664 AN: 5176

South Asian (SAS) AF: 0.243 AC: 1173 AN: 4820

European-Finnish (FIN) AF: 0.310 AC: 3278 AN: 10572

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14340 AN: 67966

Other (OTH) AF: 0.230 AC: 486 AN: 2110

Alfa AF: 0.214 Hom.: 14703

Bravo AF: 0.232

Asia WGS AF: 0.299 AC: 1039 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.64
DANN	Benign	0.60
PhyloP100		-0.90
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: rs9951012; hg19: chr18-60023794;