chr15-73887666-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_153356.3(TBC1D21):​c.824C>T​(p.Ala275Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,614,086 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000037 ( 2 hom. )

Consequence

TBC1D21
NM_153356.3 missense

Scores

3
7
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.75
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 Likely_benign. Variant got -4 ACMG points.

BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TBC1D21NM_153356.3 linkc.824C>T p.Ala275Val missense_variant Exon 9 of 11 ENST00000300504.7 NP_699187.1 Q8IYX1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TBC1D21ENST00000300504.7 linkc.824C>T p.Ala275Val missense_variant Exon 9 of 11 1 NM_153356.3 ENSP00000300504.2 Q8IYX1-1
TBC1D21ENST00000535547.6 linkc.716C>T p.Ala239Val missense_variant Exon 8 of 10 1 ENSP00000439325.2 Q8IYX1-2
TBC1D21ENST00000562056.1 linkc.713C>T p.Ala238Val missense_variant Exon 8 of 10 5 ENSP00000457096.1 H3BTA9

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152216
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:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000757
AC:
19
AN:
250876
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135644
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000555
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000369
AC:
54
AN:
1461752
Hom.:
2
Cov.:
31
AF XY:
0.0000605
AC XY:
44
AN XY:
727176
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000568
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152334
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74476
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:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.0000659
AC:
8

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 28, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.824C>T (p.A275V) alteration is located in exon 9 (coding exon 9) of the TBC1D21 gene. This alteration results from a C to T substitution at nucleotide position 824, causing the alanine (A) at amino acid position 275 to be replaced by a valine (V). 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
Pathogenic
0.71
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.20
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.036
.;T;T
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Benign
0.026
D
MetaRNN
Uncertain
0.51
D;D;D
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
1.7
.;L;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-2.1
N;N;N
REVEL
Benign
0.20
Sift
Uncertain
0.014
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.77
MutPred
0.58
.;Gain of helix (P = 0.132);.;
MVP
0.35
MPC
0.84
ClinPred
0.47
T
GERP RS
4.6
Varity_R
0.24
gMVP
0.62

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: rs779089267; hg19: chr15-74180007; API