2-101008146-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001330348.2(TBC1D8):​c.3143G>A​(p.Arg1048Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,613,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TBC1D8
NM_001330348.2 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.61
Variant links:
Genes affected
TBC1D8 (HGNC:17791): (TBC1 domain family member 8) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Apr 2022]
RPL31 (HGNC:10334): (ribosomal protein L31) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L31E family of ribosomal proteins. It is located in the cytoplasm. Higher levels of expression of this gene in familial adenomatous polyps compared to matched normal tissues have been observed. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.04022962).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TBC1D8NM_001330348.2 linkc.3143G>A p.Arg1048Gln missense_variant Exon 20 of 20 ENST00000409318.2 NP_001317277.1 J3KQ40
TBC1D8NM_001102426.3 linkc.3098G>A p.Arg1033Gln missense_variant Exon 20 of 20 NP_001095896.1 O95759-1
RPL31NM_001098577.3 linkc.346+2075C>T intron_variant Intron 4 of 4 NP_001092047.1 P62899-2
TBC1D8NR_138475.2 linkn.3109G>A non_coding_transcript_exon_variant Exon 19 of 19

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TBC1D8ENST00000409318.2 linkc.3143G>A p.Arg1048Gln missense_variant Exon 20 of 20 5 NM_001330348.2 ENSP00000386856.1 J3KQ40

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000113
AC:
28
AN:
248632
Hom.:
0
AF XY:
0.000126
AC XY:
17
AN XY:
134960
show subpopulations
Gnomad AFR exome
AF:
0.000130
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000213
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000119
AC:
174
AN:
1461542
Hom.:
0
Cov.:
34
AF XY:
0.000127
AC XY:
92
AN XY:
727024
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000143
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152260
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000229
Hom.:
0
Bravo
AF:
0.000121
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000237
AC:
2
ExAC
AF:
0.000124
AC:
15
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000297

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 22, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3098G>A (p.R1033Q) alteration is located in exon 20 (coding exon 20) of the TBC1D8 gene. This alteration results from a G to A substitution at nucleotide position 3098, causing the arginine (R) at amino acid position 1033 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.014
T;.
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.30
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.74
T;T
M_CAP
Benign
0.0054
T
MetaRNN
Benign
0.040
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Uncertain
2.1
M;.
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-1.1
N;N
REVEL
Benign
0.043
Sift
Benign
0.094
T;T
Sift4G
Benign
0.20
T;T
Polyphen
0.81
P;.
Vest4
0.15
MVP
0.24
MPC
0.41
ClinPred
0.049
T
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.059
gMVP
0.14

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201893005; hg19: chr2-101624608; API