3-17185147-A-T
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001349074.2(TBC1D5):c.1880T>A(p.Met627Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
TBC1D5
NM_001349074.2 missense
NM_001349074.2 missense
Scores
8
6
5
Clinical Significance
Conservation
PhyloP100: 8.74
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 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.829
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TBC1D5 | NM_001349074.2 | c.1880T>A | p.Met627Lys | 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.1880T>A | p.Met627Lys | missense_variant | 20/23 | NM_001349074.2 | ENSP00000512418 | P2 | ||
ENST00000649558.1 | n.699-18576A>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251358Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135830
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461390Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727020
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
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 | Oct 12, 2022 | The c.1880T>A (p.M627K) alteration is located in exon 21 (coding exon 18) of the TBC1D5 gene. This alteration results from a T to A substitution at nucleotide position 1880, causing the methionine (M) at amino acid position 627 to be replaced by a lysine (K). 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
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
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
Pathogenic
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;.;D
Vest4
MutPred
Loss of stability (P = 0.0034);Loss of stability (P = 0.0034);.;.;
MVP
MPC
0.79
ClinPred
D
GERP RS
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