18-62325387-T-TCGCGCTGCTGCTGCTCTG

Variant names:

• chr18-62325387-T-TCGCGCTGCTGCTGCTCTG
• rs886037749
• NM_003839.4:c.45_62dupGCTGCTCTGCGCGCTGCT

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PP5_Very_Strong BP3

The NM_003839.4(TNFRSF11A):​c.45_62dupGCTGCTCTGCGCGCTGCT​(p.Leu21_Ala22insLeuLeuCysAlaLeuLeu) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF11A NM_003839.4 disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.108
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PP5: Variant 18-62325387-T-TCGCGCTGCTGCTGCTCTG is Pathogenic according to our data. Variant chr18-62325387-T-TCGCGCTGCTGCTGCTCTG is described in ClinVar as Pathogenic. ClinVar VariationId is 208143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP3: Nonframeshift variant in repetitive region in NM_003839.4

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.45_62dupGCTGCTCTGCGCGCTGCT	p.Leu21_Ala22insLeuLeuCysAlaLeuLeu	disruptive_inframe_insertion	Exon 1 of 10	NP_003830.1	Q9Y6Q6-1
	TNFRSF11A	NM_001278268.2		c.45_62dupGCTGCTCTGCGCGCTGCT	p.Leu21_Ala22insLeuLeuCysAlaLeuLeu	disruptive_inframe_insertion	Exon 1 of 10	NP_001265197.1	Q9Y6Q6-6
	TNFRSF11A	NM_001270950.2		c.45_62dupGCTGCTCTGCGCGCTGCT	p.Leu21_Ala22insLeuLeuCysAlaLeuLeu	disruptive_inframe_insertion	Exon 1 of 8	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.45_62dupGCTGCTCTGCGCGCTGCT	p.Leu21_Ala22insLeuLeuCysAlaLeuLeu	disruptive_inframe_insertion	Exon 1 of 10	ENSP00000465500.1	Q9Y6Q6-1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.45_62dupGCTGCTCTGCGCGCTGCT	p.Leu21_Ala22insLeuLeuCysAlaLeuLeu	disruptive_inframe_insertion	Exon 1 of 7	ENSP00000269485.7	Q9Y6Q6-2
	TNFRSF11A	ENST00000903844.1		c.45_62dupGCTGCTCTGCGCGCTGCT	p.Leu21_Ala22insLeuLeuCysAlaLeuLeu	disruptive_inframe_insertion	Exon 1 of 10	ENSP00000573903.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Familial expansile osteolysis (1)
1	-	-	Familial expansile osteolysis;C4085251:Paget disease of bone 2, early-onset (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11
Mutation Taster		=82/18	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886037749; hg19: chr18-59992620;