18-62361793-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_003839.4(TNFRSF11A):c.730G>T(p.Ala244Ser) variant causes a missense, 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_003839.4 missense, splice_region
NM_003839.4 missense, splice_region
Scores
5
5
3
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.66
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius 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 id is 6304.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.730G>T | p.Ala244Ser | missense_variant, splice_region_variant | 7/10 | ENST00000586569.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNFRSF11A | ENST00000586569.3 | c.730G>T | p.Ala244Ser | missense_variant, splice_region_variant | 7/10 | 1 | NM_003839.4 | P2 | |
TNFRSF11A | ENST00000269485.11 | c.616+1744G>T | intron_variant | 1 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive osteopetrosis 7 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2008 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Lab, Department of Haematology, Christian Medical College | May 20, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
A;A
PrimateAI
Benign
T
Polyphen
1.0
.;.;D
Vest4
0.24, 0.28
MutPred
Gain of methylation at K240 (P = 0.0608);Gain of methylation at K240 (P = 0.0608);Gain of methylation at K240 (P = 0.0608);
MVP
0.87
MPC
0.79
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at