15-73884215-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153356.3(TBC1D21):​c.337C>T​(p.Arg113Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R113Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

TBC1D21
NM_153356.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.451
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24717185).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TBC1D21NM_153356.3 linkuse as main transcriptc.337C>T p.Arg113Trp missense_variant 4/11 ENST00000300504.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TBC1D21ENST00000300504.7 linkuse as main transcriptc.337C>T p.Arg113Trp missense_variant 4/111 NM_153356.3 P1Q8IYX1-1
TBC1D21ENST00000535547.6 linkuse as main transcriptc.229C>T p.Arg77Trp missense_variant 3/101 Q8IYX1-2
TBC1D21ENST00000562056.1 linkuse as main transcriptc.337C>T p.Arg113Trp missense_variant 4/105

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152234
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251482
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.0000615
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000150
AC:
22
AN:
1461884
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152234
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.000121
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0

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 submitterclinical testingAmbry GeneticsMay 26, 2023The c.337C>T (p.R113W) alteration is located in exon 4 (coding exon 4) of the TBC1D21 gene. This alteration results from a C to T substitution at nucleotide position 337, causing the arginine (R) at amino acid position 113 to be replaced by a tryptophan (W). 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
0.097
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.62
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.047
.;T;T
Eigen
Benign
0.11
Eigen_PC
Benign
0.12
FATHMM_MKL
Benign
0.48
N
LIST_S2
Benign
0.79
T;T;T
M_CAP
Benign
0.0078
T
MetaRNN
Benign
0.25
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.69
.;N;.
MutationTaster
Benign
0.90
N;N;N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-2.3
N;N;D
REVEL
Benign
0.066
Sift
Benign
0.034
D;D;D
Sift4G
Uncertain
0.018
D;D;D
Polyphen
0.99
.;D;.
Vest4
0.33
MutPred
0.45
.;Loss of disorder (P = 0.0425);Loss of disorder (P = 0.0425);
MVP
0.39
MPC
0.75
ClinPred
0.75
D
GERP RS
3.5
Varity_R
0.062
gMVP
0.39

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: rs745668732; hg19: chr15-74176556; API