rs796051862

chr18-62325386-T-TTCGCGCTGCTGCTGCTCTGCGCGCTGC

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.39_65dup(p.Leu14_Ala22dup) 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, single submitter P:2
• Conservation: PhyloP100: -0.0820

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 18-62325386-T-TTCGCGCTGCTGCTGCTCTGCGCGCTGC is Pathogenic according to our data. Variant chr18-62325386-T-TTCGCGCTGCTGCTGCTCTGCGCGCTGC is described in ClinVar as [Pathogenic]. Clinvar id is 6300.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.39_65dup	p.Leu14_Ala22dup	inframe_insertion	1/10	ENST00000586569.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.39_65dup	p.Leu14_Ala22dup	inframe_insertion	1/10	1	NM_003839.4	P2
TNFRSF11A	ENST00000269485.11	c.39_65dup	p.Leu14_Ala22dup	inframe_insertion	1/7	1		A2
TNFRSF11A	ENST00000592013.1	n.66_92dup		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:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2023

This variant, c.39_65dup, results in the insertion of 9 amino acid(s) of the TNFRSF11A protein (p.Leu14_Ala22dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with autosomal dominant expansile osteolytic syndromes (PMID: 10615125, 31923705; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 75dup27 and 77dup27. ClinVar contains an entry for this variant (Variation ID: 6300). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TNFRSF11A function (PMID: 10615125, 21472776). For these reasons, this variant has been classified as Pathogenic. -

Paget disease of bone 2, early-onset Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2000

- -

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: rs796051862; hg19: chr18-59992619;