18-62361793-G-T

Variant names:

• chr18-62361793-G-T
• rs121908658
• NM_003839.4:c.730G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PM2 PP3_Strong PP5_Moderate

The NM_001270950.2(TNFRSF11A):​c.730G>T​(p.Gly244*) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF11A NM_001270950.2 stop_gained, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.66
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive osteopetrosis 7

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

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

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

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

ACMG classification

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

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.28 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 18-62361793-G-T is Pathogenic according to our data. Variant chr18-62361793-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6304.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270950.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	NM_003839.4	MANE Select	c.730G>T	p.Ala244Ser	missense splice_region	Exon 7 of 10	NP_003830.1	Q9Y6Q6-1
	TNFRSF11A	NM_001278268.2		c.688G>T	p.Ala230Ser	missense splice_region	Exon 7 of 10	NP_001265197.1	Q9Y6Q6-6
	TNFRSF11A	NM_001270950.2		c.730G>T	p.Gly244*	stop_gained splice_region	Exon 7 of 8	NP_001257879.1	Q9Y6Q6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	ENST00000586569.3	TSL:1 MANE Select	c.730G>T	p.Ala244Ser	missense splice_region	Exon 7 of 10	ENSP00000465500.1	Q9Y6Q6-1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.616+1744G>T		intron	N/A	ENSP00000269485.7	Q9Y6Q6-2
	TNFRSF11A	ENST00000903844.1		c.745G>T	p.Ala249Ser	missense splice_region	Exon 7 of 10	ENSP00000573903.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal recessive osteopetrosis 7 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.27	T
PhyloP100		5.7
PrimateAI	Benign	0.43	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.24
MutPred		0.75		Gain of methylation at K240 (P = 0.0608)
MVP		0.87
MPC		0.79
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.28
gMVP		0.46
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 0

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

Other links and lift over

dbSNP: rs121908658; hg19: chr18-60029026;