4-140624142-C-A

Variant summary

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

The NM_015130.3(TBC1D9):​c.3052G>T​(p.Ala1018Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000994 in 1,609,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

TBC1D9
NM_015130.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.39
Variant links:
Genes affected
TBC1D9 (HGNC:21710): (TBC1 domain family member 9) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. [provided by Alliance of Genome Resources, Apr 2022]

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=0.06326768).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TBC1D9NM_015130.3 linkc.3052G>T p.Ala1018Ser missense_variant Exon 20 of 21 ENST00000442267.3 NP_055945.2 Q6ZT07

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TBC1D9ENST00000442267.3 linkc.3052G>T p.Ala1018Ser missense_variant Exon 20 of 21 1 NM_015130.3 ENSP00000411197.2 Q6ZT07

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152156
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000412
AC:
1
AN:
242562
Hom.:
0
AF XY:
0.00000761
AC XY:
1
AN XY:
131428
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000914
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000960
AC:
14
AN:
1457600
Hom.:
0
Cov.:
31
AF XY:
0.00000690
AC XY:
5
AN XY:
724650
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000991
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152156
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Mar 10, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3052G>T (p.A1018S) alteration is located in exon 20 (coding exon 20) of the TBC1D9 gene. This alteration results from a G to T substitution at nucleotide position 3052, causing the alanine (A) at amino acid position 1018 to be replaced by a serine (S). 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
0.081
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.061
T
Eigen
Benign
-0.20
Eigen_PC
Benign
0.025
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.74
T
M_CAP
Benign
0.0027
T
MetaRNN
Benign
0.063
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.34
N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.54
N
REVEL
Benign
0.034
Sift
Benign
0.17
T
Sift4G
Benign
0.53
T
Polyphen
0.0
B
Vest4
0.11
MutPred
0.20
Gain of phosphorylation at A1018 (P = 0.0309);
MVP
0.068
MPC
0.45
ClinPred
0.47
T
GERP RS
4.8
Varity_R
0.050
gMVP
0.20

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: rs1428320101; hg19: chr4-141545296; API