18-62325355-G-T

Variant names:

• chr18-62325355-G-T
• NM_003839.4:c.3G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003839.4(TNFRSF11A):​c.3G>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNFRSF11A NM_003839.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.257
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive osteopetrosis 7

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet
• familial expansile osteolysis

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• dysosteosclerosis

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
• osteosarcoma

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 9 pathogenic variants. Next in-frame start position is after 56 codons. Genomic position: 62349820. Lost 0.090 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-62325355-G-T is Pathogenic according to our data. Variant chr18-62325355-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3459130.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.3G>T	p.Met1?	start_lost	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.3G>T	p.Met1?	start_lost	Exon 1 of 10	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11	c.3G>T	p.Met1?	start_lost	Exon 1 of 7	1		ENSP00000269485.7
TNFRSF11A	ENST00000592013.1	n.30G>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 876194 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 412582

African (AFR) AF: 0.00 AC: 0 AN: 16494

American (AMR) AF: 0.00 AC: 0 AN: 2652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6188

East Asian (EAS) AF: 0.00 AC: 0 AN: 5350

South Asian (SAS) AF: 0.00 AC: 0 AN: 18678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1792

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 792538

Other (OTH) AF: 0.00 AC: 0 AN: 29446

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jul 12, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3G>T (p.M1?) alteration is located in coding exon 1 of the TNFRSF11A gene and consists of a G to T substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Although biallelic loss of function of TNFRSF11A has been associated with autosomal recessive TNFRSF11A -related osteopetrosis, haploinsufficiency of TNFRSF11A has not been established as a mechanism of disease for autosomal dominant TNFRSF11A-related osteolytic disorder. Based on the available evidence, the TNFRSF11A c.3G>T (p.M1?) alteration is classified as likely pathogenic for autosomal recessive TNFRSF11A -related osteopetrosis; however, the association of this alteration with autosomal dominant TNFRSF11A-related osteolytic disorder is unlikely. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.048	.;.;.;.;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Benign	-1.0	T
PhyloP100		0.26
PROVEAN	Benign	-0.54	.;N;.;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.040	.;D;.;.;.
Sift4G	Benign	0.12	.;T;T;T;T
Polyphen		0.60	.;.;.;.;P
Vest4		0.78, 0.72, 0.79, 0.73
MutPred		0.73		Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);
MVP		1.0
ClinPred		0.19	T
GERP RS		1.9
PromoterAI		-0.068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.27
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr18-59992588;