rs879253796

Positions:

• chr18-62325397-G-GCTGCTCTGCGCGCTGCTC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_003839.4(TNFRSF11A):​c.46_63dup​(p.Leu16_Leu21dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF11A NM_003839.4 inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.0170

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a signal_peptide (size 28) in uniprot entity TNR11_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003839.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-62325397-G-GCTGCTCTGCGCGCTGCTC is Pathogenic according to our data. Variant chr18-62325397-G-GCTGCTCTGCGCGCTGCTC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6299.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF11A	NM_003839.4	c.46_63dup	p.Leu16_Leu21dup	inframe_insertion	1/10	ENST00000586569.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.46_63dup	p.Leu16_Leu21dup	inframe_insertion	1/10	1	NM_003839.4	P2
TNFRSF11A	ENST00000269485.11	c.46_63dup	p.Leu16_Leu21dup	inframe_insertion	1/7	1		A2
TNFRSF11A	ENST00000592013.1	n.73_90dup		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial expansile osteolysis Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 11, 2022	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs879253796; hg19: chr18-59992630;