3-17185114-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001349074.2(TBC1D5):āc.1913A>Gā(p.His638Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,611,176 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.00013 ( 0 hom., cov: 32)
Exomes š: 0.0000075 ( 0 hom. )
Consequence
TBC1D5
NM_001349074.2 missense
NM_001349074.2 missense
Scores
2
11
6
Clinical Significance
Conservation
PhyloP100: 7.50
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]
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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/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TBC1D5 | NM_001349074.2 | c.1913A>G | p.His638Arg | missense_variant | 20/23 | ENST00000696125.1 | NP_001336003.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TBC1D5 | ENST00000696125.1 | c.1913A>G | p.His638Arg | missense_variant | 20/23 | NM_001349074.2 | ENSP00000512418 | P2 | ||
ENST00000649558.1 | n.699-18609T>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250902Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135586
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GnomAD4 exome AF: 0.00000754 AC: 11AN: 1458972Hom.: 0 Cov.: 30 AF XY: 0.00000689 AC XY: 5AN XY: 725764
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GnomAD4 genome AF: 0.000131 AC: 20AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74356
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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 submitter | clinical testing | Ambry Genetics | Jan 30, 2024 | The c.1913A>G (p.H638R) alteration is located in exon 21 (coding exon 18) of the TBC1D5 gene. This alteration results from a A to G substitution at nucleotide position 1913, causing the histidine (H) at amino acid position 638 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Benign
T;T;T;D
Polyphen
D;D;.;D
Vest4
MVP
MPC
0.69
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at