NM_003839.4:c.1568-43C>T

Variant names:

• chr18-62384708-C-T
• rs56231704
• NM_003839.4:c.1568-43C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003839.4(TNFRSF11A):​c.1568-43C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,598,578 control chromosomes in the GnomAD database, including 51,277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3348 hom., cov: 29)
  • Exomes 𝑓: 0.24 (47929 hom.)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.142
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 18-62384708-C-T is Benign according to our data. Variant chr18-62384708-C-T is described in ClinVar as Benign. ClinVar VariationId is 259179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.27 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.1568-43C>T		intron	N/A	NP_003830.1	Q9Y6Q6-1
	TNFRSF11A	NM_001278268.2		c.1526-43C>T		intron	N/A	NP_001265197.1	Q9Y6Q6-6
	TNFRSF11A	NM_001270950.2		c.731-43C>T		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.1568-43C>T		intron	N/A	ENSP00000465500.1	Q9Y6Q6-1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.617-43C>T		intron	N/A	ENSP00000269485.7	Q9Y6Q6-2
	TNFRSF11A	ENST00000903844.1		c.1583-43C>T		intron	N/A	ENSP00000573903.1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27396 AN: 151560 Hom.: 3345 Cov.: 29

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.00274

Gnomad SAS AF: 0.0677

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.212

GnomAD2 exomes AF: 0.180 AC: 40995 AN: 227680 AF XY: 0.183

Gnomad AFR exome AF: 0.0419

Gnomad AMR exome AF: 0.137

Gnomad ASJ exome AF: 0.258

Gnomad EAS exome AF: 0.000564

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.265

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.245 AC: 353933 AN: 1446898 Hom.: 47929 Cov.: 32 AF XY: 0.240 AC XY: 172690 AN XY: 718120

African (AFR) AF: 0.0394 AC: 1309 AN: 33244

American (AMR) AF: 0.145 AC: 6273 AN: 43406

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 6518 AN: 25774

East Asian (EAS) AF: 0.000584 AC: 23 AN: 39368

South Asian (SAS) AF: 0.0805 AC: 6733 AN: 83610

European-Finnish (FIN) AF: 0.190 AC: 9978 AN: 52390

Middle Eastern (MID) AF: 0.170 AC: 975 AN: 5742

European-Non Finnish (NFE) AF: 0.280 AC: 308726 AN: 1103616

Other (OTH) AF: 0.224 AC: 13398 AN: 59748

GnomAD4 genome AF: 0.181 AC: 27403 AN: 151680 Hom.: 3348 Cov.: 29 AF XY: 0.173 AC XY: 12818 AN XY: 74120

African (AFR) AF: 0.0498 AC: 2064 AN: 41418

American (AMR) AF: 0.190 AC: 2899 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 904 AN: 3464

East Asian (EAS) AF: 0.00275 AC: 14 AN: 5090

South Asian (SAS) AF: 0.0679 AC: 327 AN: 4814

European-Finnish (FIN) AF: 0.179 AC: 1888 AN: 10556

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18543 AN: 67784

Other (OTH) AF: 0.215 AC: 452 AN: 2100

Alfa AF: 0.158 Hom.: 470

Bravo AF: 0.177

Asia WGS AF: 0.0820 AC: 288 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.90
PhyloP100		0.14
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: rs56231704; hg19: chr18-60051941;