chr18-62325363-GCGCCCGGCGGCGC-G

Variant names:

• chr18-62325363-GCGCCCGGCGGCGC-G
• rs1338132991
• NM_003839.4:c.18_30delGCGGCGCCGCCCG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_003839.4(TNFRSF11A):​c.18_30delGCGGCGCCGCCCG​(p.Arg7CysfsTer172) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000679 in 147,330 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R6R) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
• Consequence: TNFRSF11A NM_003839.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.47

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

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.
• PP5: Variant 18-62325363-GCGCCCGGCGGCGC-G is Pathogenic according to our data. Variant chr18-62325363-GCGCCCGGCGGCGC-G is described in ClinVar as [Pathogenic]. Clinvar id is 2794042.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.18_30delGCGGCGCCGCCCG	p.Arg7CysfsTer172	frameshift_variant	Exon 1 of 10	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.18_30delGCGGCGCCGCCCG	p.Arg7CysfsTer172	frameshift_variant	Exon 1 of 10	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11	c.18_30delGCGGCGCCGCCCG	p.Arg7CysfsTer172	frameshift_variant	Exon 1 of 7	1		ENSP00000269485.7
TNFRSF11A	ENST00000592013.1	n.45_57delGCGGCGCCGCCCG		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.00000679 AC: 1 AN: 147330 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000673

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000679 AC: 1 AN: 147330 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 71728

African (AFR) AF: 0.00 AC: 0 AN: 40930

American (AMR) AF: 0.0000673 AC: 1 AN: 14852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66242

Other (OTH) AF: 0.00 AC: 0 AN: 2034

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Oct 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg7Cysfs*172) in the TNFRSF11A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TNFRSF11A are known to be pathogenic (PMID: 10677500, 18606301, 22271396). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TNFRSF11A-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=52/148	disease causing (fs/PTC)

Splicing

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

Publications

Loading publications...

Other links and lift over

dbSNP: rs1338132991; hg19: chr18-59992596;