3-17160983-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001349074.2(TBC1D5):​c.2434G>T​(p.Val812Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 0.000070 ( 0 hom. )

Consequence

TBC1D5
NM_001349074.2 missense

Scores

5
7
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.30
Variant links:
Genes affected
TBC1D5 (HGNC:19166): (TBC1 domain family member 5) Enables AP-2 adaptor complex binding activity and retromer complex binding activity. Involved in several processes, including macroautophagy; positive regulation of receptor internalization; and retrograde transport, endosome to Golgi. Located in Golgi apparatus; autophagosome; and endosome membrane. Part of retromer complex. Colocalizes with AP-2 adaptor complex and Atg1/ULK1 kinase complex. [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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.34853607).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TBC1D5NM_001349074.2 linkuse as main transcriptc.2434G>T p.Val812Leu missense_variant 23/23 ENST00000696125.1 NP_001336003.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TBC1D5ENST00000696125.1 linkuse as main transcriptc.2434G>T p.Val812Leu missense_variant 23/23 NM_001349074.2 ENSP00000512418 P2Q92609-2
ENST00000649558.1 linkuse as main transcriptn.698+5491C>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152202
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:
0.00000797
AC:
2
AN:
250960
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135648
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000705
AC:
103
AN:
1461626
Hom.:
0
Cov.:
31
AF XY:
0.0000646
AC XY:
47
AN XY:
727088
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.0000908
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152202
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74346
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
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000189
TwinsUK
AF:
0.000539
AC:
2
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 GeneticsMar 25, 2024The c.2434G>T (p.V812L) alteration is located in exon 24 (coding exon 21) of the TBC1D5 gene. This alteration results from a G to T substitution at nucleotide position 2434, causing the valine (V) at amino acid position 812 to be replaced by a leucine (L). 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
0.62
BayesDel_addAF
Uncertain
0.099
D
BayesDel_noAF
Uncertain
-0.080
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.018
T;T;.
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.90
.;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.35
T;T;T
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
0.81
L;L;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-1.3
N;N;N
REVEL
Benign
0.27
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.67
P;P;.
Vest4
0.59
MutPred
0.20
Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;
MVP
0.53
MPC
0.62
ClinPred
0.72
D
GERP RS
5.6
Varity_R
0.58
gMVP
0.50

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: rs761752878; hg19: chr3-17202475; API