11-67404275-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001369496.1(TBC1D10C):​c.73G>T​(p.Asp25Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,604,356 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

TBC1D10C
NM_001369496.1 missense

Scores

4
8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.89
Variant links:
Genes affected
TBC1D10C (HGNC:24702): (TBC1 domain family member 10C) The protein encoded by this gene has an N-terminal Rab-GTPase domain and a binding site at the C-terminus for calcineurin, and is an inhibitor of both the Ras signaling pathway and calcineurin, a phosphatase regulated by calcium and calmodulin. Genes encoding similar proteins are located on chromosomes 16 and 22. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2013]
PPP1CA (HGNC:9281): (protein phosphatase 1 catalytic subunit alpha) The protein encoded by this gene is one of the three catalytic subunits of protein phosphatase 1 (PP1). This broadly expressed gene encodes the alpha subunit of the PP1 complex that associates with over 200 regulatory proteins to form holoenzymes which dephosphorylate their biological targets with high specificity. PP1 is a serine/threonine specific protein phosphatase known to be involved in the regulation of a variety of cellular processes, such as cell division, glycogen metabolism, muscle contractility, protein synthesis, and HIV-1 viral transcription. Increased PP1 activity has been observed in the end stage of heart failure. Studies suggest that PP1 is an important regulator of cardiac function and that PP1 deregulation is implicated in diabetes and multiple types of cancer. Three alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2020]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TBC1D10CNM_001369496.1 linkc.73G>T p.Asp25Tyr missense_variant Exon 1 of 9 ENST00000542590.2 NP_001356425.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TBC1D10CENST00000542590.2 linkc.73G>T p.Asp25Tyr missense_variant Exon 1 of 9 1 NM_001369496.1 ENSP00000443654.1 Q8IV04-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152114
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
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:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000122
AC:
3
AN:
245164
Hom.:
0
AF XY:
0.0000150
AC XY:
2
AN XY:
133774
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000293
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:
0.000335
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1452242
Hom.:
0
Cov.:
31
AF XY:
0.00000832
AC XY:
6
AN XY:
720816
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000900
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:
0.00000452
Gnomad4 OTH exome
AF:
0.000100
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152114
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.000178
ExAC
AF:
0.00000825
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 08, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.73G>T (p.D25Y) alteration is located in exon 2 (coding exon 1) of the TBC1D10C gene. This alteration results from a G to T substitution at nucleotide position 73, causing the aspartic acid (D) at amino acid position 25 to be replaced by a tyrosine (Y). 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
0.73
BayesDel_addAF
Benign
-0.013
T
BayesDel_noAF
Benign
-0.17
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Benign
0.37
.;.;T
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Pathogenic
0.99
.;D;D
M_CAP
Benign
0.015
T
MetaRNN
Uncertain
0.44
T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Uncertain
2.4
M;M;M
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-5.7
D;D;D
REVEL
Benign
0.28
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0030
D;D;D
Polyphen
1.0
.;.;D
Vest4
0.55
MutPred
0.21
Gain of phosphorylation at D25 (P = 0.0172);Gain of phosphorylation at D25 (P = 0.0172);Gain of phosphorylation at D25 (P = 0.0172);
MVP
0.42
MPC
0.86
ClinPred
0.91
D
GERP RS
5.0
Varity_R
0.71
gMVP
0.65

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: rs148408200; hg19: chr11-67171746; API