15-73886571-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_153356.3(TBC1D21):c.736C>T(p.Arg246Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
TBC1D21
NM_153356.3 missense
NM_153356.3 missense
Scores
3
3
13
Clinical Significance
Conservation
PhyloP100: 1.22
Genes affected
TBC1D21 (HGNC:28536): (TBC1 domain family member 21) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.793
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBC1D21 | NM_153356.3 | c.736C>T | p.Arg246Cys | missense_variant | 8/11 | ENST00000300504.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBC1D21 | ENST00000300504.7 | c.736C>T | p.Arg246Cys | missense_variant | 8/11 | 1 | NM_153356.3 | P1 | |
TBC1D21 | ENST00000535547.6 | c.628C>T | p.Arg210Cys | missense_variant | 7/10 | 1 | |||
TBC1D21 | ENST00000562056.1 | c.625C>T | p.Arg209Cys | missense_variant | 7/10 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152228Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251420Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135882
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GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461388Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17AN XY: 726988
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74366
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 26, 2022 | The c.736C>T (p.R246C) alteration is located in exon 8 (coding exon 8) of the TBC1D21 gene. This alteration results from a C to T substitution at nucleotide position 736, causing the arginine (R) at amino acid position 246 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
.;L;.
MutationTaster
Benign
N;N;N
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D
REVEL
Benign
Sift
Pathogenic
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
0.98
.;D;.
Vest4
MutPred
0.74
.;Loss of MoRF binding (P = 0.0349);.;
MVP
MPC
0.95
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at