chr20-440250-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_144628.4(TBC1D20):c.766G>A(p.Val256Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000999 in 1,611,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000075 ( 0 hom. )
Consequence
TBC1D20
NM_144628.4 missense, splice_region
NM_144628.4 missense, splice_region
Scores
2
7
10
Splicing: ADA: 0.9659
2
Clinical Significance
Conservation
PhyloP100: 5.79
Genes affected
TBC1D20 (HGNC:16133): (TBC1 domain family member 20) This gene encodes a protein that belongs to a family of GTPase activator proteins of Rab-like small GTPases. The encoded protein and its cognate GTPase, Rab1, bind the nonstructural protein 5A (NS5A) of the hepatitis C virus (HCV) to mediate viral replication. Depletion of this protein inhibits replication of the virus and HCV infection. Mutations in this gene are associated with Warburg micro syndrome 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]
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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
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBC1D20 | NM_144628.4 | c.766G>A | p.Val256Met | missense_variant, splice_region_variant | 6/8 | ENST00000354200.5 | |
TBC1D20 | NR_111901.2 | n.894G>A | splice_region_variant, non_coding_transcript_exon_variant | 6/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBC1D20 | ENST00000354200.5 | c.766G>A | p.Val256Met | missense_variant, splice_region_variant | 6/8 | 1 | NM_144628.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000335 AC: 51AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000126 AC: 31AN: 246594Hom.: 0 AF XY: 0.0000973 AC XY: 13AN XY: 133604
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GnomAD4 exome AF: 0.0000754 AC: 110AN: 1459662Hom.: 0 Cov.: 30 AF XY: 0.0000730 AC XY: 53AN XY: 726028
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GnomAD4 genome AF: 0.000335 AC: 51AN: 152270Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30AN XY: 74452
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 28, 2015 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 13, 2023 | The c.766G>A (p.V256M) alteration is located in exon 6 (coding exon 6) of the TBC1D20 gene. This alteration results from a G to A substitution at nucleotide position 766, causing the valine (V) at amino acid position 256 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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
Find out detailed SpliceAI scores and Pangolin per-transcript scores at