rs886037749

chr18-62325387-T-TCGCGCTGCTGCTGCTCTG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_003839.4(TNFRSF11A):c.45_62dup(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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF11A NM_003839.4 inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.108

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 Pathogenic. Variant got 12 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 18-62325387-T-TCGCGCTGCTGCTGCTCTG is Pathogenic according to our data. Variant chr18-62325387-T-TCGCGCTGCTGCTGCTCTG is described in ClinVar as [Pathogenic]. Clinvar id is 208143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF11A	NM_003839.4	c.45_62dup	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.45_62dup	p.Leu16_Leu21dup	inframe_insertion	1/10	1	NM_003839.4	P2
TNFRSF11A	ENST00000269485.11	c.45_62dup	p.Leu16_Leu21dup	inframe_insertion	1/7	1		A2
TNFRSF11A	ENST00000592013.1	n.72_89dup		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial expansile osteolysis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2007

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects TNFRSF11A function (PMID: 10615125, 21472776). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 208143). This variant is also known as 83dup18, 84dup18. This variant, c.45_62dup, results in the insertion of 6 amino acid(s) to the TNFRSF11A protein (p.Leu16_Leu21dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individuals with autosomal dominant familial expansile osteolysis (PMID: 10615125, 12568416, 17447113). It has also been observed to segregate with disease in related individuals. -

Familial expansile osteolysis;C4085251:Paget disease of bone 2, early-onset Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jun 03, 2016

- -

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: rs886037749; hg19: chr18-59992620;